Akt3 modulators

Abstract

To provide a new compound useful for treating cachexia or wasting syndrome which is a severe complication of chronic diseases such as neurodegenerative diseases and cancer.SOLUTION: Compounds of formula Ib or Ic are described. The compounds can modify the Akt3 or effects of nature in vitro or in vivo, and can also be used, alone or in combination with other agents, in the prevention or treatment of various conditions.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 021,987, filed May 8, 2020, and U.S. Provisional Application No. 63 / 121,001, filed December 3, 2020, the contents of each of which are incorporated herein by reference in their entirety.

[0002] Incorporation by Citation Any patents, patent publications, publications, or other documents cited herein are expressly incorporated herein by reference in their entirety.

[0003] FIELD OF THE INVENTION The present invention relates generally to Akt3 modulators and methods of treating and preventing diseases through modulation of Akt3 signaling. [Background technology]

[0004] Background of the Invention Chronic diseases and disorders are persistent conditions that require ongoing treatment and generally negatively impact a patient's quality of life. Chronic diseases are the leading cause of disability and death in the United States. Common chronic diseases include, but are not limited to, heart disease, cancer, neurodegenerative diseases, diabetes, obesity, eating disorders, and arthritis. It is estimated that roughly 6 in 10 adults in the United States have a chronic disease, and 4 in 10 have two or more chronic diseases. Chronic diseases are also a leading driver of annual healthcare costs in the United States, totaling $3.3 trillion (see "About Chronic Diseases," National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention; updated October 23, 2019). These statistics highlight the need for new and improved treatments and preventive interventions for diseases such as cancer, inflammatory diseases, neurodegenerative diseases, pathogenic infections, immunodeficiency disorders, weight gain disorders, weight loss disorders, hormone imbalances, tuberous sclerosis, retinitis pigmentosa, and congestive heart failure.

[0005] Neurodegenerative diseases are debilitating conditions characterized by the progressive degeneration and death of nerve cells, also called neurons. Neurons are components of the nervous system and normally do not self-replenish after injury or death. The loss or dysfunction of neurons in patients with neurodegenerative diseases can affect body movement and brain function. Neurodegenerative diseases include, but are not limited to, Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, multiple sclerosis, prion diseases, motor neuron disease, spinocerebellar ataxia, and spinal muscular atrophy. The symptoms of advanced neurodegenerative diseases can be devastating, causing patients to lose memory, motor control, and personality. Existing treatments for neurodegenerative diseases can manage symptoms but generally cannot prevent or cure the disease. These existing treatments typically have negative side effects that further worsen patients' quality of life.

[0006] A severe complication of chronic diseases such as neurodegenerative diseases and cancer is cachexia, or wasting syndrome. Cachexia is defined as a weight loss of more than 5% of body weight within 12 months in the presence of a chronic illness. Other symptoms of cachexia include muscle atrophy, fatigue, weakness, and often loss of appetite. The weight loss associated with cachexia is due to a loss of muscle mass as well as fat. Patients with cachexia often lose weight even while still eating a normal diet. As with neurodegenerative diseases, there is currently no effective treatment for cachexia, which is responsible for many chronic disease-related deaths. Summary of the Invention [Problem to be solved by the invention]

[0007] Thus, there is an unmet need for more effective and acceptable treatments and preventative interventions for these and other diseases and disease-related complications. [Means for solving the problem]

[0008] Summary of the Invention As used herein, Akt3 refers to the RAC-gammaserine / threonine-protein kinase, an enzyme encoded by the Akt3 gene in humans. In some embodiments, the Akt3 protein is represented by Formula Ia, Ib, or Ic. [ka] or a salt thereof, wherein the various substituents are defined herein. In certain embodiments, the compounds can modulate the properties or effects of Akt3 in vitro or in vivo and / or can be used alone or in combination with other agents to prevent or treat a variety of conditions. In other embodiments, methods of synthesizing the compounds are provided. In other aspects, pharmaceutical compositions comprising the compounds and methods of using these compositions alone or in combination with other agents or compositions to prevent or treat a variety of conditions are also described herein.

[0009] In some embodiments, a compound of formula Ia, Ib, or Ic [ka] or a pharmaceutically acceptable salt thereof, where: [ka] teeth [ka] and X1, X2, X3, X4, X5, X6, X7, X8 and X9 are independently at each occurrence CR1 or N; R1 is H, D, halogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) haloalkenyl, (C2-C6) alkynyl, (C2-C6) haloalkynyl, (C3-C7) cycloalkyl, (C4-C 10 )bicycloalkyl, (C3-C7)heterocycloalkyl, halogenated (C3-C7)heterocycloalkyl, (C4-C 10 )heterobicycloalkyl, (C4-C 10 ) Heterospiroalkyl, aryl, heteroaryl, -OR a , -SR a , -N(R a )2, -COR a , -CO2R a , CON(R a )2, -CN, -NC, NO2, N3, -SO2R a , -SO2N(R a )2, -N(R a )SO2R a , [ka] and optionally one or more of (C1-C6) alkyl, halogenated (C1-C6) alkyl, -SO2R a or -SO2N(R a ) 2 substituted partially saturated bicyclic heteroaryl; wherein R1 is (C3-C7)cycloalkyl, (C4-C 10 )bicycloalkyl, (C3-C7)heterocycloalkyl, (C4-C 10 )heterobicycloalkyl, (C4-C 10 ) Heterospiroalkyl, aryl and heteroaryl each optionally include one or more of (C1-C6) alkyl, halogenated (C1-C6) alkyl, halogen, -OR a , -CN or -N(R a )2 is substituted; n is an integer from 0 to 4 depending on the valence; Q is C(R a )2, O, NR a , N(C=O)R a or NSO2R a and; Y1, Y2, Y3, Y4 and Y5 are each independently N or CR2, depending on valence; R2 is H, halogen, D, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) haloalkenyl, (C2-C6) alkynyl, (C2-C6) haloalkynyl, (C3-C7) cycloalkyl, (C4-C 10 )bicycloalkyl, (C3-C7)heterocycloalkyl, halogenated (C3-C7)heterocycloalkyl, (C4-C 10 )heterobicycloalkyl, (C4-C 10 ) Heterospiroalkyl, aryl, heteroaryl, -OR a , -SR a , -N(R a )2, -COR a , -CO2R a , CON(R a )2, -CN, -NC, NO2, N3, -SO2R a , -SO2N(R a )2, -N(R a )SO2R a , [ka] selected from the group consisting of: -EG- is -(C=O)NR x -, -NR x (C=O)-, -N(R x )(C=O)N(R x )-, -O(C=O)N(R x )-, -N(R x )(C=O)O-, -SO2NR x -, -NR x SO2- or [ka] where R x is independently at each occurrence H, (C-C)alkyl, (C-C)cycloalkyl, aryl, or heteroaryl; or R x and Y3, R x and Y4, R x and Z1 or R x and Z4 together form an optionally substituted 5- to 6-membered heterocycle; W1, W2, W3, W4 and W5 are each independently CR6, N or NR6, depending on the valence available; R6, independently at each occurrence, is selected from the group consisting of H, halogen, (C1-C6) alkyl, and (C1-C6) haloalkyl; T is independently in each occurrence O, N, or NR depending on the valence. a , N(C=O)R a , NC(R b )2OP(=O)(OR b )2 or NSO2R a and; U in each occurrence independently represents O, N, or NR depending on the valence. a , N(C=O)R a , NC(R b )2OP(=O)(OR b )2 or NSO2R a and; R b is independently at each occurrence H or (C-C) alkyl; Z1, Z2, Z3, Z4 and Z5 are each independently N or CR3 where valence allows; R3 is H, D, halogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) haloalkenyl, (C2-C6) alkynyl, (C2-C6) haloalkynyl, (C3-C7) cycloalkyl, (C4-C 10 )bicycloalkyl, (C3-C7)heterocycloalkyl, halogenated (C3-C7)heterocycloalkyl, (C4-C 10 )heterobicycloalkyl, (C4-C 10 ) Heterospiroalkyl, aryl, heteroaryl, -OR a , -SR a , -N(R a )2, -COR a , -CO2R a , CON(R a )2, -CN, -NC, NO2, N3, -SO2R a , -SO2N(R a )2, -N(R a )SO2R a , [ka] selected from the group consisting of: V is absent, C(R a )2, NR a , N(C=O)R a , NSO2R a or O; R4 is (C1-C6) alkyl, (C3-C7) cycloalkyl, (C4-C 10 )bicycloalkyl, (C3-C7)heterocycloalkyl, (C4-C 10 )heterobicycloalkyl, (C4-C 10 ) selected from the group consisting of heterospiroalkyl, aryl, and heteroaryl, each optionally substituted with one or more R5; or alternatively, V and R4 together are (C3-C7)heterocycloalkyl or (C4-C 10 ) forming a heterospiroalkyl; R5, independently at each occurrence, is H, D, halogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) haloalkenyl, (C2-C6) alkynyl, (C2-C6) haloalkynyl, (C3-C7) cycloalkyl, (C4-C 10 )bicycloalkyl, (C3-C7)heterocycloalkyl, halogenated (C3-C7)heterocycloalkyl, (C4-C 10 )heterobicycloalkyl, (C4-C 10 ) Heterospiroalkyl, aryl, heteroaryl, -OR a , -SR a , -N(R a )2, -COR a , -CO2R a , CON(R a )2, -CN, -NC, NO2, N3, -SO2R a , -SO2N(R a )2, -N(R a )SO2R a , N(R a )COR a , [ka] selected from the group consisting of: R a is independently at each occurrence H, (C-C) alkyl, (C-C) alkenyl, (C-C) cycloalkyl, aryl, or heteroaryl, or two R a together form a 4- to 6-membered ring optionally substituted with halogen or (C1-C6) alkyl.

[0010] In any of the embodiments disclosed herein, Q, T, and U are each independently O, NH, NCH3, N(C=O)H, N(C=O)CH3, N(C=O)CH2CH3, NSO2CH3, or NSO2CH2CH3.

[0011] In any of the embodiments disclosed herein, X1, X2, X3, X4, X5, X6, X7, X8, X9, Y1, Y2, Y3, Y4, Y5, Z1, Z2, Z3, Z4 and Z5 are each independently CH or N.

[0012] In any of the embodiments disclosed herein, [ka] teeth [ka] is.

[0013] In any of the embodiments disclosed herein, the structural moiety [ka] teeth [ka] It has the following structure.

[0014] In any of the embodiments disclosed herein, n is 0, 1, or 2.

[0015] In any of the embodiments disclosed herein, the structural moiety [ka] teeth [ka] It has the following structure.

[0016] In any of the embodiments disclosed herein, the structural moiety [ka] teeth [ka] It has the following structure.

[0017] In any of the embodiments disclosed herein, [ka] teeth [ka] is.

[0018] In any of the embodiments disclosed herein, the structural moiety [ka] teeth [ka] It has the following structure.

[0019] In any of the embodiments disclosed herein, n is 0, 1, or 2.

[0020] In any of the embodiments disclosed herein, the structural moiety [ka] teeth [ka] It has the following structure.

[0021] In any of the embodiments disclosed herein, the structural moiety [ka] teeth [ka] It has the following structure.

[0022] In any of the embodiments disclosed herein, the structural moiety [ka] teeth [ka] It has the following structure.

[0023] In any of the embodiments disclosed herein, [ka] teeth [ka] is.

[0024] In any of the embodiments disclosed herein, the structural moiety [ka] teeth [ka] It has the following structure.

[0025] In any of the embodiments disclosed herein, the structural moiety [ka] teeth [ka] It has the following structure.

[0026] In any of the embodiments disclosed herein, Q is O.

[0027] In any of the embodiments disclosed herein, Q is NR a , N(C=O)R a or NSO2R a is.

[0028] In any of the embodiments disclosed herein, R1 is independently at each occurrence H, D, halogen, OR a, N(R a )2, (C1-C6) alkyl, (C1-C6) alkynyl, (C3-C7) heterocycloalkyl, (C4-C 10 ) Heterospiroalkyl, halogenated (C3-C7)heterocycloalkyl, aryl, (C4-C 10 ) Bicycloalkyl, -CN, -NC, N3, NO2, COR a , CO2R a , CON(R a )2, -SO2R a or -SO2N(R a )2; wherein the (C3-C7)heterocycloalkyl is optionally substituted with one or more (C1-C6)alkyl.

[0029] In any of the embodiments disclosed herein, R1, independently at each occurrence, is H, halogen, (C1-C6) alkyl, (C3-C7) heterocycloalkyl, (C4-C 10 )heterospiroalkyl, halogenated (C3-C7)heterocycloalkyl, N(R a )2 or -CN; wherein the (C3-C7)heterocycloalkyl is optionally substituted with one or more (C1-C6)alkyl.

[0030] In any of the embodiments disclosed herein, R1 is, independently at each occurrence, H, (C1-C6)alkyl, (C1-C6)alkyl, halogenated (C3-C7)heterocycloalkyl, or (C3-C7)heterocycloalkyl; wherein the (C3-C7)heterocycloalkyl is optionally substituted with one or more (C1-C6)alkyl.

[0031] In any of the embodiments disclosed herein, R1, independently at each occurrence, is H, D, F, Cl, Br, CH3, OCH3, NH2, NHCH3, N(CH3)2, [ka] is.

[0032] In any of the embodiments disclosed herein, at least one of R1 is [ka] [ka] [ka] In any of the embodiments disclosed herein, [ka] teeth [ka] is.

[0033] In any of the embodiments disclosed herein, R1, independently at each occurrence, is H, D, F, CH3, NH2, NHCH3, N(CH3)2, [ka] is.

[0034] In any of the embodiments disclosed herein, the structural moiety [ka] teeth [ka] where Q is O or NH.

[0035] In any of the embodiments disclosed herein, the structural moiety [ka] teeth [ka] where Q is O or NH.

[0036] In any of the embodiments disclosed herein, the structural moiety [ka] teeth [ka] wherein Q is O or NH and R1 is H, (C1-C6) alkyl, (C3-C7) heterocycloalkyl, halogenated (C3-C7) heterocycloalkyl or halogen.

[0037] In any of the embodiments disclosed herein, the structural moiety [ka] teeth [ka] where Q is O or NH.

[0038] In any of the embodiments disclosed herein, the structural moiety [ka] teeth [ka] where Q is O or NH.

[0039] In any of the embodiments disclosed herein, the compound has the formula of Formula Ia:

[0040] In any of the embodiments disclosed herein, the structural moiety [ka] teeth [ka] It has the following structure.

[0041] In any of the embodiments disclosed herein, the structural moiety [ka] teeth [ka] It has the following structure.

[0042] In any of the embodiments disclosed herein, R2 is, independently at each occurrence, H, halogen, CH3, CF3, OH, NH2, -NHCH3, or -N(CH3)2.

[0043] In any of the embodiments disclosed herein, the structural moiety [ka] teeth [ka] It has the following structure.

[0044] In any of the embodiments disclosed herein, the structural moiety [ka] teeth [ka] It has the following structure.

[0045] In any of the embodiments disclosed herein, the structural moiety [ka] teeth [ka] It has the following structure.

[0046] In any of the embodiments disclosed herein, the structural moiety [ka] teeth [ka] It has the following structure.

[0047] In any of the embodiments disclosed herein, the structural moiety [ka] teeth [ka] It has the following structure.

[0048] In any of the embodiments disclosed herein, the structural moiety [ka] teeth [ka] It has the following structure.

[0049] In any of the embodiments disclosed herein, the structural moiety [ka] teeth [ka] It has the following structure.

[0050] In any of the embodiments disclosed herein, R3, at each occurrence, is H, halogen, CH3, CF3, OH, NH2, -NHCH3, or -N(CH3)2.

[0051] In any of the embodiments disclosed herein, the moiety [ka] teeth [ka] It has the following structure.

[0052] In any of the embodiments disclosed herein, the structural moiety [ka] teeth [ka] where R3 is H, CH3, OH, halogen, or NH2; x is H, CH3 or CH2CH3.

[0053] In any of the embodiments disclosed herein, the structural moiety [ka] teeth [ka] where m is independently in each occurrence 1 or 2 and J is C(R y )2 and R y is independently at each occurrence H, (C1-C6)alkyl, OH, O(C1-C6)alkyl, or halogen.

[0054] In any of the embodiments disclosed herein, the structural moiety [ka] teeth [ka] wherein Y1, Y2, Y3, and Y4 are each independently N, CH, CCH3, or CF.

[0055] In any of the embodiments disclosed herein, the structural moiety [ka] teeth [ka] where m is independently in each occurrence 1 or 2 and J is C(R z )2 and R z is independently at each occurrence H, (C1-C6)alkyl, OH, O(C1-C6)alkyl, or halogen.

[0056] In any of the embodiments disclosed herein, the structural moiety [ka] teeth [ka] wherein Z1, Z2, Z3, and Z4 are each independently N, CH, CCH3, or CF.

[0057] In any of the embodiments disclosed herein, the compound has the formula of Formula Ib:

[0058] In any of the embodiments disclosed herein, the structural moiety [ka] teeth [ka] where T and U are independently in each occurrence O, N, NR, or any of the valence-dependent a , N(C=O)R a , NC(R b )2OP(=O)(OR b )2 or NSO2R a is.

[0059] In any of the embodiments disclosed herein, the structural moiety [ka] teeth [ka] where R3 is H, CH3, OH, halogen, or NH2; a is H, CH3 or CH2CH3.

[0060] In any of the embodiments disclosed herein, the structural moiety [ka] teeth [ka] It has the following structure.

[0061] In any of the embodiments disclosed herein, R b is independently at each occurrence H or (C1-C6) alkyl.

[0062] In any of the embodiments disclosed herein, R b is independently at each occurrence H, CH3, CH2CH3, or CH(CH3)2.

[0063] In any of the embodiments disclosed herein, the compound has the formula of Formula Ic:

[0064] In any of the embodiments disclosed herein, the structural moiety [ka] teeth [ka] where T and U are independently in each occurrence O, N, NR, or any of the valence-dependent a , N(C=O)R a , NC(R b )2OP(=O)(OR b )2 or NSO2Ra is.

[0065] In any of the embodiments disclosed herein, the structural moiety [ka] teeth [ka] where R2 is H, CH3, OH, halogen, or NH2; a is H, CH3 or CH2CH3.

[0066] In any of the embodiments disclosed herein, the structural moiety [ka] teeth [ka] It has the following structure.

[0067] In any of the embodiments disclosed herein, R b is independently at each occurrence H or (C1-C6) alkyl.

[0068] In any of the embodiments disclosed herein, R b is independently at each occurrence H, CH3, CH2CH3, or CH(CH3)2.

[0069] In any of the embodiments disclosed herein, R2 is, independently at each occurrence, H, CH3, OH, NH2, or halogen.

[0070] In any of the embodiments disclosed herein, the structural moiety [ka] teeth [ka] It has the following structure.

[0071] In any of the embodiments disclosed herein, the structural moiety [ka] teeth [ka] It has the following structure.

[0072] In any of the embodiments disclosed herein, the structural moiety [ka] teeth [ka] It has the following structure.

[0073] In any of the embodiments disclosed herein, the structural moiety [ka] V and R4 are united (C4-C 10 ) forming a heterospiroalkyl.

[0074] In any of the embodiments disclosed herein, V is absent.

[0075] In any of the embodiments disclosed herein, R4 is (C1-C6) alkyl; [ka] where m is an integer of 0 to 3.

[0076] In any of the embodiments disclosed herein, R5 is independently at each occurrence H, (C1-C6) alkyl, halogen, OR a , OH, NH2, N(R a )COR a , CN, CF3, (C1-C6)haloalkyl or [ka] and R a is independently at each occurrence H, (C2-C6)alkenyl, or (C1-C6)alkyl.

[0077] In any of the embodiments disclosed herein, the structural moiety [ka] teeth [ka] where V is C(R a )2, O, NR a , N(C=O)R a or NSO2R a and V' is CR a Or N.

[0078] In any of the embodiments disclosed herein, R5 is independently at each occurrence H, CH3, halogen, OH, CN, [ka] CF3, (C1-C6)haloalkyl or NH2.

[0079] In any of the embodiments disclosed herein, R a is independently at each occurrence H, (C2-C6)alkenyl, or (C1-C6)alkyl.

[0080] In any of the embodiments disclosed herein, R a is H, CH3, or CH2CH3 in each occurrence.

[0081] In any of the embodiments disclosed herein, the structural moiety [ka] teeth [ka] It has the following structure.

[0082] In any of the embodiments disclosed herein, the structural moiety [ka] teeth [ka] It has the following structure.

[0083] In any of the embodiments disclosed herein, the compound of formula Ia is [ka] [ka] where R1 is H, (C1-C6) alkyl, N(R a )2, (C3-C7)heterocycloalkyl or halogen; R5 and R 11 are each independently H or CH; Y, Y, Y, Y, Z, Z, Z, L, and L are each independently CH or N; and V is NH or O.

[0084] In any of the embodiments disclosed herein, R1 is H, F, Cl, Br, CH3, CH2CH3, CH(CH3)2, NH2, NMe2, [ka] is.

[0085] In any of the embodiments disclosed herein, the compound of formula Ib is [ka] where R 11and R5 are each independently H or CH3; and Y1, Y2, Y3, Y4, Z2, Z3 and Z4 are each independently CH or N.

[0086] In any of the embodiments disclosed herein, the compound of formula Ia is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] is.

[0087] In any of the embodiments disclosed herein, the compound of formula Ib is [ka] [ka] is.

[0088] In any of the embodiments disclosed herein, the compound of formula Ic is [ka] is.

[0089] In any of the embodiments disclosed herein, the compound is [ka] is.

[0090] In any of the embodiments disclosed herein, the compound is selected from the group consisting of compounds 2-22 of Examples 2-22, respectively.

[0091] In another aspect, methods of treating a disease in a subject in need thereof are described, comprising administering to the subject an effective amount of a compound of any of the embodiments disclosed herein.

[0092] In any of the embodiments described herein, the disease is selected from the group consisting of neurodegenerative diseases, cachexia, eating disorders, obesity, complications of obesity, inflammatory diseases, virally induced inflammatory responses, Gulf War syndrome, tuberous sclerosis, retinitis pigmentosa, transplant rejection, cancer, autoimmune diseases, ischemic tissue injury, traumatic tissue injury, and combinations thereof.

[0093] In any of the embodiments described herein, the disease is a neurodegenerative disease.

[0094] In any of the embodiments described herein, the neurodegenerative disease is selected from the group consisting of Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, motor neuron disease, Huntington's disease, HIV-induced neurodegeneration, Lewy body disease, spinal muscular atrophy, prion disease, spinocerebellar ataxia, familial amyloidotic polyneuropathy, multiple sclerosis, and combinations thereof.

[0095] In any of the embodiments described herein, the disorder is cachexia or an eating disorder.

[0096] In any of the embodiments described herein, the disorder is obesity or a complication of obesity.

[0097] In any of the embodiments described herein, the complication of obesity is selected from the group consisting of glucose intolerance, fatty liver, dyslipidemia, and combinations thereof.

[0098] In any of the embodiments described herein, the disease is an inflammatory disease.

[0099] In any of the embodiments described herein, the inflammatory disease is selected from the group consisting of atopic dermatitis, allergies, asthma, and combinations thereof.

[0100] In any of the embodiments described herein, the disease is a virally induced inflammatory response.

[0101] In any of the embodiments described herein, the virus-induced inflammatory response is SARS-induced inflammatory pneumonia, coronavirus disease 2019, or a combination thereof.

[0102] In any of the embodiments described herein, the disease is Gulf War syndrome or tuberous sclerosis complex.

[0103] In any of the embodiments described herein, the disease is retinitis pigmentosa or graft rejection.

[0104] In any of the embodiments described herein, the condition is ischemic tissue injury or traumatic tissue injury.

[0105] In any of the embodiments described herein, the disease is cancer.

[0106] In any of the embodiments described herein, the cancer is selected from the group consisting of adult T-cell leukemia / lymphoma, bladder, brain, breast, cervical, colorectal, esophageal, kidney, liver, lung, nasopharyngeal, pancreatic, prostate, skin, stomach, uterine, ovarian, and testicular cancer.

[0107] In any of the embodiments described herein, the cancer is leukemia.

[0108] In any of the embodiments described herein, the leukemia is adult T-cell leukemia / lymphoma.

[0109] In any of the embodiments described herein, the adult T-cell leukemia / lymphoma is caused by a human T-cell lymphotropic virus.

[0110] In any of the embodiments described herein, the disease is an autoimmune disease.

[0111] In any of the embodiments described herein, the autoimmune disease is selected from the group consisting of achalasia, Addison's disease, adult Still's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-glomerular basement membrane disease, anti-tubular basement membrane nephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmune dysautonomia, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease, autoimmune myocarditis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune urticaria, axonal and neuronal neuropathy, Baro's disease, Behçet's disease, benign mucosal Pemphigoid, Castleman's disease, celiac disease, Chagas' disease, chronic inflammatory demyelinating polyneuropathy, chronic relapsing multifocal osteomyelitis, Churg-Strauss syndrome, eosinophilic granulomatosis, cicatricial pemphigoid, Cogan's syndrome, cold agglutinin disease, congenital heart block, Coxsackie-myocarditis, CREST syndrome, Crohn's disease, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus, Dressler's syndrome, endometriosis, eosinophilic esophagitis, eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, Evans' syndrome, fibromyalgia, fibrotic lung Folliculitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture's syndrome, granulomatosis with polyangiitis, Graves' disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schönlein purpura, pemphigoid of pregnancy, hidradenitis suppurativa (acne inversa), hypogammaglobulinemia, IgA nephropathy, IgG4-related sclerosing disease, immune thrombocytopenic purpura, inclusion body myositis, interstitial cystitis, juvenile arthritis, juvenile diabetes mellitus (type 1 diabetes), juvenile myositis, Kawasaki disease, Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosus, lignified conjunctivitis, linear IgA disease, lupus, chronic Lyme disease, Meniere's disease, microscopic polyangiitis, mixed connective tissue disease, Mooren's ulcer, Mukka-Habermann disease, multifocal motor neuropathy, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neonatal lupus, neuromyelitis optica, neutropenia, ocular cicatricial pemphigoid, optic neuritis, relapsing rheumatism, pediatric autoimmune neuropsychiatric disorders, paraneoplastic cerebellar degeneration, paroxysmal nocturnal hemoglobinuria, Parry-Romberg syndrome, pars planitis (peripheral uveitis), Parsonage-Turner syndrome, pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia,POEMS syndrome, polyarteritis nodosa, polyglandular syndrome type I, polyglandular syndrome type II, polyglandular syndrome type III, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, post-pericardiotomy syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, progestational dermatitis, psoriasis, psoriatic arthritis, pure red cell aplasia, pyoderma gangrenosum, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, relapsing polychondritis, restless legs syndrome, retroperitoneal fibrosis, rheumatic fever, joint The disease is selected from the group consisting of rheumatoid arthritis, sarcoidosis, Schmidt's syndrome, scleritis, scleroderma, Sjogren's syndrome, sperm and testicular autoimmunity, stiff-body syndrome, subacute bacterial endocarditis, Susac's syndrome, sympathetic ophthalmia, Takayasu's arteritis, temporal arteritis (giant cell arteritis), thrombocytopenic purpura, Tolosa-Hunt syndrome, transverse myelitis, ulcerative colitis, undifferentiated connective tissue disease, uveitis, vasculitis, leukoplakia, Vogt-Koyanagi-Harada disease, and combinations thereof.

[0112] In any of the embodiments described herein, the compound modulates Akt3 in immune cells.

[0113] In any of the embodiments described herein, the immune cells are selected from the group consisting of T cells, B cells, macrophages, and glial cells.

[0114] In any of the embodiments described herein, the glial cells are astrocytes, microglia, or oligodendrocytes.

[0115] In any of the embodiments described herein, the T cells are T regulatory cells.

[0116] In any of the embodiments described herein, the compound activates Akt3 signaling.

[0117] In any of the embodiments described herein, the compound inhibits Akt3 signaling.

[0118] In any of the embodiments described herein, the compound increases T regulatory cell activity or production.

[0119] In any of the embodiments described herein, the compound reduces T regulatory cell activity or production.

[0120] In any of the embodiments described herein, the method further comprises administering to the subject a second therapeutic agent.

[0121] In any of the embodiments described herein, the second therapeutic agent is selected from the group consisting of nutritional supplementation, chemotherapy, anti-inflammatory agents, immunosuppressants, cholinesterase inhibitors, antidepressants, anxiolytics, antipsychotics, riluzole, edaravone, dopamine agonists, MAO B inhibitors, catechol O-methyltransferase inhibitors, anticholinergics, anticonvulsants, tetrabenazine, carbidopa-levodopa, antispasmodics, antibodies, fusion proteins, enzymes, nucleic acids, ribonucleic acids, antiproliferative agents, cytotoxic agents, appetite stimulants, 5-HT3 antagonists, Cox-2 inhibitors, and combinations thereof.

[0122] In any of the embodiments described herein, the method further includes treating the subject with an immunotherapeutic agent, an immune modulator, a costimulatory activating agonist, a cytokine, a chemokine, a chemokine factor, an oncolytic virus, a biologic, a vaccine, a small molecule, a targeted therapy, an anti-inflammatory agent, a cell therapy, a chemotherapeutic agent, or radiation therapy.

[0123] Any of the embodiments disclosed herein may be appropriately combined with any of the other embodiments disclosed herein. Combinations of any of the embodiments disclosed herein with any of the other embodiments disclosed herein are expressly contemplated. Specifically, one or more embodiments of one substituent may be appropriately combined with one or more specific embodiments of any other substituent. Such combinations may be implemented in any one or more of the embodiments of the present application described herein or in any of the formulas described herein. [Brief explanation of the drawings]

[0124] The present application will now be described with reference to the following figures, which are provided for purposes of illustration only and are not intended to be limiting.

[0125]

Figure 1

[0126] Detailed Description of the Invention definition It should be recognized that the present invention is not limited to the compositions and methods described herein and the experimental conditions described, as these may vary. It should also be understood that the terminology used herein is used for the purpose of describing certain embodiments only and is not intended to be limiting, since the scope of the present invention is limited only by the appended claims.

[0127] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Any compositions, methods, and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention.

[0128] The use of the singular in describing the invention claimed herein (particularly in the claims) should be construed to encompass both the singular and the plural unless otherwise stated herein or clearly contradicted by context.

[0129] The recitation of ranges of values ​​herein, unless otherwise stated herein, is intended to serve merely as a shorthand method of referring to each individual value falling within that range, and each separate value is included herein to the same extent as if it were individually referred to herein.

[0130] The use of the term "about" is intended to refer to values ​​within a range of about ±10% above and below the stated value. In certain embodiments, values ​​may range about ±5% above and below the stated value. In certain embodiments, values ​​may range about ±2% above and below the stated value. In other embodiments, values ​​may range about ±1% above and below the stated value. The foregoing ranges are intended to be clear from the context and do not imply further limitation. All methods described herein may be performed in any suitable order unless otherwise specified herein or clearly contrary to the context. Any and all examples or exemplary language provided herein (e.g., "exemplary," "such as," "for example," "including but not limited to") are intended solely to facilitate easier understanding of the invention and do not pose limitations on the scope of the invention, unless otherwise specified.

[0131] The following are definitions of terms used herein. The first definition provided for a group or term applies to that group or term throughout this specification, individually or as part of another group, unless otherwise specified. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0132] The terms "alkyl" and "alk" refer to a straight or branched chain alkane (hydrocarbon) radical containing 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms. Examples of "alkyl" groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, and the like. The term "(C 1-"C4) alkyl" refers to a straight or branched chain alkane (hydrocarbon) radical containing 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, and isobutyl. "Substituted alkyl" refers to an alkyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Examples of substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents, in the latter case forming a CF3- or CCl3-bearing alkyl group), cyano, nitro, oxo (i.e., =0), CF3, OCF3, cycloalkyl, bicycloalkyl, spiroalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(=O)2R e , P(=O)2R e , S(=O)2OR e , -N=S(=O)(R a ), S(=O)(=NR a )(=N(R a )2) (attached to the molecule via S or N), P(=O)2OR e , N.R. b R c , N.R. b S(=O)2R e , N.R. b P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NR b R c , N.R. d S(=O)2NR b Rc , N.R. d P(=O)NR b R c , N.R. b C(=O)R a or NR b P(=O)2R e , where R a is independently at each occurrence hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c and R d is independently at each occurrence hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b and R c may be taken together with the N to which they are attached to form a heterocycle, and R e is independently at each occurrence alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. In certain embodiments, groups such as alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, heterocycle, and aryl can themselves be optionally substituted.

[0133] The term "heteroalkyl" refers to a straight- or branched-chain alkyl group preferably having 2 to 12 carbons, more preferably 2 to 10 carbons, in the chain, one or more of which are replaced by a heteroatom selected from the group consisting of S, O, P, and N. Examples of heteroalkyls include, but are not limited to, alkyl ethers, secondary and tertiary alkyl amines, alkyl sulfides, and the like. The group can be a terminal group or a bridging group.

[0134] The term "alkenyl" refers to a straight or branched chain hydrocarbon radical containing 2 to 12 carbon atoms and at least one carbon-carbon double bond. Examples of such groups include ethenyl or allyl. The term "C2-C6 alkenyl" includes ethylenyl, propenyl, 2-propenyl, (E)-but-2-enyl, (Z)-but-2-enyl, 2-methy(E)-but-2-enyl, 2-methy(Z)-but-2-enyl, 2,3-dimethylbut-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z)-hex-1-enyl, (E)-pent- "Alkenyl" refers to a straight or branched chain hydrocarbon radical containing 2 to 6 carbon atoms and at least one carbon-carbon double bond, such as 2-enyl, (Z)-hex-2-enyl, (E)-hex-2-enyl, (Z)-hex-1-enyl, (E)-hex-1-enyl, (Z)-hex-3-enyl, (E)-hex-3-enyl, and (E)-hex-1,3-dienyl. "Substituted alkenyl" refers to an alkenyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Examples of substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen, alkyl, halogenated alkyl (i.e., an alkyl group bearing a single halogen substituent or multiple halogen substituents such as CF3 or CCl3), cyano, nitro, oxo (i.e., =0), CF3, OCF3, cycloalkyl, bicycloalkyl, spiroalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(=O)2R e , -N=S(=O)(R a ), -R a S(=O)(=NR a ), S(=O)(=NR a )(=N(R a )2)(R a or bonded to the molecule via N), P(=O)2R e , S(=O)2OR e , P(=O)2OR e , N.R. b R c , N.R. b S(=O)2Re , N.R. b P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NR b R c , N.R. d S(=O)2NR b R c , N.R. d P(=O)NR b R c , N.R. b C(=O)R a or NR b P(=O)2R e , where R a is independently at each occurrence hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c and R d is independently at each occurrence hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b and R c optionally form a heterocycle together with the N to which they are attached; and R e is independently at each occurrence alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. The exemplary substituents may themselves be optionally substituted.

[0135] The term "alkynyl" refers to a straight-chain or branched-chain hydrocarbon radical containing 2 to 12 carbon atoms and at least one carbon-carbon triple bond. Exemplary groups include ethynyl. The term "C2-C6 alkynyl" refers to a straight-chain or branched-chain hydrocarbon radical containing 2 to 6 carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, pent-1-ynyl, pent-2-ynyl, hex-1-ynyl, hex-2-ynyl, or hex-3-ynyl. "Substituted alkynyl" refers to an alkynyl substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Examples of substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents, in the latter case forming a CF3 or CCl3 bearing alkyl group), cyano, nitro, oxo (i.e., =0), CF3, OCF3, cycloalkyl, bicycloalkyl, spiroalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(=O)2R e , P(=O)2R e , S(=O)2OR e , -N=S(=O)(R a ), -R a S(=O)(=NR a ), S(=O)(=NR a )(=N(R a )2)(R a or bonded to the molecule via N), P(=O)2OR e , N.R. b R c , N.R. b S(=O)2R e , N.R. b P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O)R a , C(=O)NRb R c , OC(=O)R a , OC(=O)NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NR b R c , N.R. d S(=O)2NR b R c , N.R. d P(=O)NR b R c , N.R. b C(=O)R a or NR b P(=O)2R e , where R a is independently at each occurrence hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c and R d is independently at each occurrence hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b and R c optionally form a heterocycle together with the N to which they are attached; and R e is independently at each occurrence alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. The exemplary substituents may themselves be optionally substituted.

[0136] The term "cycloalkyl" refers to a fully saturated cyclic hydrocarbon group containing 1 to 4 rings and 3 to 8 carbons per ring. "C3-C7 cycloalkyl" refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. "Substituted cycloalkyl" refers to a cycloalkyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Examples of substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents, in the latter case forming a CF3 or CCl3 bearing alkyl group), cyano, nitro, oxo (i.e., =0), CF3, OCF3, cycloalkyl, bicycloalkyl, spiroalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(=O)2R e , -N=S(=O)(R a ), -R a S(=O)(=NR a ), S(=O)(=NR a )(=N(R a )2)(R a or bonded to the molecule via N), P(=O)2R e , S(=O)2OR e , P(=O)2OR e , N.R. b R c , N.R. b S(=O)2R e , N.R. b P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , N.R. b C(=O)OR e , N.R. dC(=O)NR b R c , N.R. d S(=O)2NR b R c , N.R. d P(=O)NR b R c , N.R. b C(=O)R a or NR b P(=O)2R e , where R a is independently at each occurrence hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c and R d is independently at each occurrence hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b and R c optionally form a heterocycle together with the N to which they are attached; and R e is independently at each occurrence alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. Exemplary substituents may themselves be optionally substituted. Examples of substituents also include spiro-linked or fused ring substituents, particularly spiro-linked cycloalkyl, spiro-linked cycloalkenyl, spiro-linked heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the cycloalkyl, cycloalkenyl, heterocycle, and aryl substituents may themselves be optionally substituted.

[0137] The term "bicycloalkyl" or "spiroalkyl" refers to a compound containing at least one cycloalkyl ring that shares one or more ring atoms with at least one other cycloalkyl ring. The term "heterobicycloalkyl" or "heterospiroalkyl" refers to a bicycloalkyl group in which at least one, preferably 1 to 3, carbon atoms of at least one ring are replaced with a heteroatom selected from the group consisting of N, S, O, or P. Examples of bicycloalkyl groups, in which the heteroatoms can be at terminal or bridging positions (i.e., at the point of attachment of the two rings), include adamantyl, bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.1.1]hexyl, octahydropentalenyl, bicyclo[3.2.1]octyl, bicyclo[3.3.3]undecanyl, decahydronaphthalenyl, bicyclo[3.2.0]heptyl, octahydro-1H-indenyl, bicyclo[4.2.1]nonanyl, etc. Examples of spirobicycloalkyl groups include spiro[4.4]nonyl, spiro[3.3]heptyl, spiro[5.5]undecyl, spiro[3.5]nonyl, spiro[4.5]decyl, etc. "Substituted bicycloalkyl," "substituted spiroalkyl," "substituted heterobicycloalkyl," and "substituted heterospiroalkyl" refer to a bicycloalkyl, spiroalkyl, heterobicycloalkyl, or heterospiroalkyl group that is substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Examples of substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents, in the latter case forming a CF3- or CCl3-bearing alkyl group), cyano, nitro, oxo (i.e., =0), CF3, OCF3, cycloalkyl, bicycloalkyl, spiroalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(=O)2R e , -N=S(=O)(R a ), -R a S(=O)(=NR a ), S(=O)(=NRa )(=N(R a )2)(R a or bonded to the molecule via N), P(=O)2R e , S(=O)2OR e , P(=O)2OR e , N.R. b R c , N.R. b S(=O)2R e , N.R. b P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NR b R c , N.R. d S(=O)2NR b R c , N.R. d P(=O)NR b R c , N.R. b C(=O)R a or NR b P(=O)2R e , where R a is independently at each occurrence hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c and R d is independently at each occurrence hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b and R c optionally form a heterocycle together with the N to which they are attached; and R eis independently at each occurrence alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. Exemplary substituents may themselves be optionally substituted. Examples of substituents also include spiro-linked or fused ring substituents, particularly spiro-linked cycloalkyl, spiro-linked cycloalkenyl, spiro-linked heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the cycloalkyl, cycloalkenyl, heterocycle, and aryl substituents may themselves be optionally substituted.

[0138] The term "heterocycloalkyl" or "cycloheteroalkyl" refers to a saturated or partially saturated monocyclic, bicyclic, or polycyclic ring containing at least one heteroatom selected from the group consisting of nitrogen, sulfur, and oxygen, preferably 1 to 3 heteroatoms, in at least one ring. Each ring preferably has 3 to 10 members, more preferably 4 to 7 members. Examples of suitable heterocycloalkyl substituents include, but are not limited to, azetidinyl, oxetanyl, pyrrolidyl, tetrahydrofuryl, tetrahydrothiofuranyl, piperidyl, piperazyl, tetrahydropyranyl, morpholino, 1,3-diazepanyl, 1,4-diazepanyl, 1,4-oxazepanyl, and 1,4-oxathiapanyl. The group may be a terminal group or a bridging group.

[0139] The term "cycloalkenyl" refers to a partially unsaturated cyclic hydrocarbon group containing 1 to 4 rings and 3 to 8 carbons per ring. Examples of such groups include cyclobutenyl, cyclopentenyl, cyclohexenyl, and the like. "Substituted cycloalkenyl" refers to a cycloalkenyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Examples of substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents, in the latter case forming a CF3- or CCl3-bearing alkyl group), cyano, nitro, oxo (i.e., =0), CF3, OCF3, cycloalkyl, bicycloalkyl, spiroalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(=O)2R e , -N=S(=O)(R a ), -R a S(=O)(=NR a ), S(=O)(=NR a )(=N(R a )2)(R a or bonded to the molecule via N), P(=O)2R e , S(=O)2OR e , P(=O)2OR e , N.R. b R c , N.R. b S(=O)2R e , N.R. b P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NRb R c , N.R. d S(=O)2NR b R c , N.R. d P(=O)NR b R c , N.R. b C(=O)R a or NR b P(=O)2R e , where R a is independently at each occurrence hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c and R d is independently at each occurrence hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b and R c optionally form a heterocycle together with the N to which they are attached; and R e is independently at each occurrence alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. Exemplary substituents may themselves be optionally substituted. Examples of substituents also include spiro-linked or fused ring substituents, particularly spiro-linked cycloalkyl, spiro-linked cycloalkenyl, spiro-linked heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the cycloalkyl, cycloalkenyl, heterocycle, and aryl substituents may themselves be optionally substituted.

[0140] The term "aryl" refers to a cyclic, aromatic hydrocarbon group having one to five aromatic rings, particularly a monocyclic or bicyclic group such as phenyl, biphenyl, or naphthyl. When containing two or more aromatic rings (e.g., bicyclic), the aromatic rings of the aryl group can be joined at a single point (e.g., biphenyl) or fused (e.g., naphthyl, phenanthrenyl, etc.). The term "fused aromatic ring" refers to a molecular structure having two or more aromatic rings, in which two adjacent aromatic rings have two carbon atoms in common. "Substituted aryl" refers to an aryl group substituted with one or more substituents, preferably one to three substituents, at any available point of attachment. Examples of substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents, in the latter case forming a CF3 or CCl3 bearing alkyl group), cyano, nitro, oxo (i.e., =0), CF3, OCF3, cycloalkyl, bicycloalkyl, spiroalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(=O)2R e , -N=S(=O)(R a ), -R a S(=O)(=NR a ), S(=O)(=NR a )(=N(R a )2)(R a or bonded to the molecule via N), P(=O)2R e , S(=O)2OR e , P(=O)2OR e , N.R. b R c , N.R. b S(=O)2R e , N.R. b P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)Ra , OC(=O)NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NR b R c , N.R. d S(=O)2NR b R c , N.R. d P(=O)NR b R c , N.R. b C(=O)R a or NR b P(=O)2R e , where R a is independently at each occurrence hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c and R d is independently at each occurrence hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b and R c optionally form a heterocycle together with the N to which they are attached; and R e is independently at each occurrence alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. Exemplary substituents may themselves be optionally substituted. Examples of substituents also include fused cyclic groups, particularly fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the cycloalkyl, cycloalkenyl, heterocycle, and aryl substituents may themselves be optionally substituted.

[0141] The term "biaryl" refers to two aryl groups linked by a single bond. The term "biheteroaryl" refers to two heteroaryl groups linked by a single bond. Similarly, the term "heteroaryl-aryl" refers to a heteroaryl group and an aryl group linked by a single bond, and the term "aryl-heteroaryl" refers to an aryl group and a heteroaryl group linked by a single bond. In some embodiments, the number of ring atoms in the heteroaryl and / or aryl rings is used to specify the size of the aryl or heteroaryl ring in a substituent. For example, 5,6-heteroaryl-aryl refers to a substituent in which a 5-membered heteroaryl is bonded to a 6-membered aryl group. Other combinations and ring sizes can be similarly specified.

[0142] The term "carbocycle" or "carbon ring" refers to a fully saturated or partially saturated cyclic hydrocarbon group containing 1 to 4 rings and 3 to 8 carbons per ring, or a cyclic, aromatic hydrocarbon group having 1 to 5 aromatic rings, particularly a monocyclic or bicyclic group such as phenyl, biphenyl, or naphthyl. The term "carbocycle" includes cycloalkyl, cycloalkenyl, cycloalkynyl, and aryl as defined above. The term "substituted carbocycle" refers to a carbocycle or carbocyclic group substituted at any available point of attachment with one or more substituents, preferably 1 to 4 substituents. Examples of substituents include, but are not limited to, those described above for substituted cycloalkyl, substituted cycloalkenyl, substituted cycloalkynyl, and substituted aryl. Examples of substituents also include spiro-linked or fused ring substituents at any one or more of the available points of attachment, particularly spiro-linked cycloalkyl, spiro-linked cycloalkenyl, spiro-linked heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, wherein the cycloalkyl, cycloalkenyl, heterocycle, and aryl substituents may themselves be optionally substituted.

[0143] The terms "heterocycle" and "heterocyclic" refer to fully saturated or partially saturated or fully unsaturated, including aromatic (i.e., "heteroaryl"), cyclic groups (e.g., 3- to 7-membered monocyclic, 7- to 11-membered bicyclic, or 8- to 16-membered tricyclic ring systems) having at least one heteroatom in at least one carbon atom-containing ring. Each ring of a heterocyclic group can independently be saturated or partially or fully unsaturated. Each ring of a heteroatom-containing heterocyclic group can have 1, 2, 3, or 4 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur atoms, where the nitrogen and sulfur heteroatoms can be optionally oxidized and the nitrogen heteroatom can be optionally quaternized. (The term "heteroarylium" refers to a heteroaryl group bearing a quaternary nitrogen atom, hence a positive charge.) A heterocyclic group can be attached to the remainder of the molecule at any heteroatom or carbon atom of the ring or ring system. Examples of monocyclic heterocyclic groups are azetidinyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, Examples of aryl include 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, hexahydrodiazepinyl, 4-piperidonyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, tetrazolyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane, and tetrahydro-1,1-dioxothienyl.Examples of bicyclic heterocyclic groups are indolyl, indolinyl, isoindolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzothienyl, benzo[d][1,3]dioxolyl, dihydro-2H-benzo[b][1,4]oxazine, 2,3-dihydrobenzo[b][1,4]dioxinyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, benzyl, benzo[b][1,4]dioxinyl, benzo[b][1,4]dioxinyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzo[b][1,4]diox ... Examples of tricyclic heterocyclic groups include benzofurazanyl, dihydrobenzo[d]oxazole, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (e.g., furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl, or furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (e.g., 3,4-dihydro-4-oxo-quinazolinyl), triazinylazepinyl, tetrahydroquinolinyl, and the like. Examples of tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl, and the like. The term "partially saturated bicyclic heteroaryl" refers to a partially saturated bicyclic heteroaryl, for example, having a saturated cycloalkyl or heterocyclic alkyl ring.

[0144] "Substituted heterocycle" and "substituted heterocyclic" (e.g., "substituted heteroaryl") refer to a heterocycle or heterocyclic group that is substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Examples of substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents, in the latter case forming a CF3 or CCl3 bearing alkyl group), cyano, nitro, oxo (i.e., =0), CF3, OCF3, cycloalkyl, bicycloalkyl, spiroalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(=O)2R e , -N=S(=O)(R a ), -R aS(=O)(=NR a ), S(=O)(=NR a )(=N(R a )2)(R a or bonded to the molecule via N), P(=O)2R e , S(=O)2OR e , P(=O)2OR e , N.R. b R c , N.R. b S(=O)2R e , N.R. b P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NR b R c , N.R. d S(=O)2NR b R c , N.R. d P(=O)NR b R c , N.R. b C(=O)R a or NR b P(=O)2R e , where R a is independently at each occurrence hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c and R d is independently at each occurrence hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b and R c optionally form a heterocycle together with the N to which they are attached; and R eis independently at each occurrence alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. Exemplary substituents may themselves be optionally substituted. Examples of substituents also include spiro-linked or fused ring substituents at any one or more available points of attachment, particularly spiro-linked cycloalkyl, spiro-linked cycloalkenyl, spiro-linked heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, where the cycloalkyl, cycloalkenyl, heterocycle, and aryl substituents may themselves be optionally substituted.

[0145] The term "oxo" can be attached to a carbon ring atom of a carbocyclic or heterocyclic ring. [ka] When an oxo substituent is attached to a carbon ring atom of an aromatic group, e.g., an aryl or heteroaryl, the bonds of the aromatic ring can be rearranged to satisfy valence requirements. For example, a pyridine having a 2-oxo substituent is [ka] When it can have the structure [ka] and its tautomeric forms.

[0146] The term "alkylamino" refers to a group having the structure -NHR', where R' is hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, as defined herein. Examples of alkylamino groups include, but are not limited to, methylamino, ethylamino, n-propylamino, iso-propylamino, cyclopropylamino, n-butylamino, tert-butylamino, neopentylamino, n-pentylamino, hexylamino, cyclohexylamino, and the like.

[0147] The term "dialkylamino" refers to a group having the structure -NRR', where R and R' are each independently alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, or heterocycle or substituted heterocycle, as defined above. R and R' can be the same or different in the dialkylamino moiety. Examples of dialkylamino groups include, but are not limited to, dimethylamino, methylethylamino, diethylamino, methylpropylamino, di(n-propyl)amino, di(isopropyl)amino, di(cyclopropyl)amino, di(n-butyl)amino, di(tert-butyl)amino, di(neopentyl)amino, di(n-pentyl)amino, di(hexyl)amino, di(cyclohexyl)amino, and the like. In certain embodiments, R and R' are linked to form a cyclic structure. The resulting cyclic structure can be aromatic or non-aromatic. Examples of the resulting cyclic structures include, but are not limited to, aziridinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyrrolyl, imidazolyl, 1,2,4-triazolyl, and tetrazolyl.

[0148] The term "halogen" or "halo" refers to chlorine, bromine, fluorine or iodine.

[0149] The term "substituted" refers to embodiments in which a molecule, molecular moiety, or substituent (e.g., an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl group, or any other group disclosed herein) is substituted with one or more substituents, preferably 1 to 6 substituents, at any available point of attachment, where valence allows. Examples of substituents include, but are not limited to, one or more of the following groups: hydrogen, halogen (e.g., a single halogen substituent or multiple halo substituents, in the latter case forming a CF3- or CCl3-bearing alkyl group), cyano, nitro, oxo (i.e., =0), CF3, OCF3, alkyl, halogen-substituted alkyl, cycloalkyl, bicycloalkyl, spiroalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aryl, OR a , S.R. a, S(=O)R e , S(=O)2R e , P(=O)2R e , S(=O)2OR e , -N=S(=O)(R a ), -R a S(=O)(=NR a ), S(=O)(=NR a )(=N(R a )2)(R a or bonded to the molecule via N), P(=O)2OR e , N.R. b R c , N.R. b S(=O)2R e , N.R. b P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NR b R c , N.R. d S(=O)2NR b R c , N.R. d P(=O)NR b R c , N.R. b C(=O)R a or NR b P(=O)2R e , where R a is independently at each occurrence hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c and R d is independently at each occurrence hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b and Rc optionally form a heterocycle together with the N to which they are attached; and R e is independently at each occurrence alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. In the above examples of substituents, groups such as alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, heterocycle, and aryl may themselves be optionally substituted. The term "optionally substituted" refers to embodiments in which a molecule, molecular moiety, or substituent (e.g., alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl group, or any other group disclosed herein) may or may not be substituted with one or more of the above-described substituents.

[0150] Unless otherwise specified, any heteroatom with unsatisfied valences is presumed to have enough hydrogen atoms to satisfy the valences.

[0151] The compounds of the present invention can form salts, which are also within the scope of the present invention. Reference to a compound of the present invention is understood to include reference to its salts, unless otherwise specified. As used herein, the term "salt" refers to acidic and / or basic salts formed with inorganic and / or organic acids and bases. Furthermore, when a compound of the present invention contains both a basic moiety, such as, but not limited to, pyridine or imidazole, and an acidic moiety, including, but not limited to, a carboxylic acid, zwitterions ("internal salts") may be formed and are included within the scope of the term "salt" as used herein. While pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, other salts may be useful, for example, in isolation or purification steps and may be used during preparation. Salts of the compounds of the present invention can be obtained, for example, by reacting a compound described herein with a certain amount, such as an equivalent amount, of an acid or base in a medium such as one in which the salt precipitates or in an aqueous medium, followed by lyophilization.

[0152] The compounds of the present invention that contain a basic moiety, such as, but not limited to, an amine, pyridine, or imidazole ring, can form salts with a variety of organic and inorganic acids. Examples of acid addition salts include acetate (e.g., those formed with acetic acid or trihaloacetic acid; e.g., trifluoroacetic acid), adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, acetate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, hydroxyethanesulfonate, and the like. Included are sulfonates (e.g., 2-hydroxyethanesulfonate), lactate, maleate, methanesulfonate, naphthalenesulfonate (e.g., 2-naphthalenesulfonate), nicotinate, nitrate, oxalate, pectinate, persulfate, phenylpropionate (e.g., 3-phenylpropionate), phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate (e.g., formed with sulfuric acid), sulfonate, tartrate, thiocyanate, toluenesulfonate such as tosylate, undecanoate, and the like.

[0153] The compounds of the present invention that contain an acidic moiety, such as a carboxylic acid, can form salts with a variety of organic and inorganic bases. Examples of base salts include alkali metal salts such as ammonium salt, sodium salt, lithium salt, and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, salts with organic bases (e.g., organic amines) such as benzathine, dicyclohexylamine, hydrabamine (formed with N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glucamide, t-butylamine, and salts with amino acids such as arginine and lysine. Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfate), long chain halides (e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), aralkyl halides (e.g., benzyl and phenethyl bromide), and the like.

[0154] Prodrugs and solvates of the compounds of the present invention are also contemplated herein. As used herein, the term "prodrug" refers to a compound that, upon administration to a subject, undergoes a metabolic chemical conversion or chemical process to produce a compound of the present invention or a salt and / or solvate thereof. Solvates of the compounds of the present invention include, for example, hydrates.

[0155] The compounds of the present invention and their salts or solvates may exist in tautomeric forms (e.g., as an amide or iminol). All such tautomeric forms are contemplated herein as part of the present invention. As used herein, any depicted structure of a compound includes all such tautomeric forms.

[0156] All stereoisomers of the present compounds, including enantiomeric and diastereomeric forms (e.g., those that may exist due to asymmetric carbon atoms of various substituents), are contemplated within the scope of the present invention. Individual stereoisomers of the compounds of the present invention may, for example, be substantially free of other isomers (e.g., pure or substantially pure optical isomers having the specified activity) or may be, for example, racemic or mixed with all other or selected stereoisomers. The chiral centers of the present invention may have the S or R configuration as defined by the International Union of Pure and Applied Chemistry (IUPAC) 1974 Recommendations. Racemates can be resolved by physical methods, such as fractional crystallization, separation, or crystallization of diastereomeric derivatives, or by separation by chiral column chromatography. Individual optical isomers can be obtained from the racemates by any suitable method, including, but not limited to, conventional methods, such as, for example, salt formation with an optically active acid followed by crystallization.

[0157] Following their preparation, the compounds of the invention are preferably isolated and purified to obtain compositions comprising 90% or more, e.g., 95% or more, 99% or more, by weight of the compound (a "substantially pure" compound), which can then be used or formulated as described herein. Such "substantially pure" compounds of the invention are also contemplated as part of the invention.

[0158] All configurational isomers of the compounds of the present invention are contemplated, in admixture or in pure or substantially pure form. The definition of the compounds of the present invention includes cis (Z) and trans (E) alkene isomers, as well as cis and trans isomers of cyclic hydrocarbon or heterocyclic rings.

[0159] Throughout the specification, groups and substituents thereof may be chosen to provide stable moieties and compounds.

[0160] Definitions of certain functional groups and chemical terms are described in more detail herein. For purposes of the present invention, chemical elements are defined as defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, pp. 75 th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic modification and specific functional moieties and reactivities are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito (1999), the entire contents of which are incorporated herein by reference.

[0161] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. All such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof, are included within the scope of the present invention. Additional asymmetric carbon atoms may be present in a substituent, such as an alkyl group. All such isomers and mixtures thereof are intended to be included in the present invention.

[0162] Isomeric mixtures containing any of a variety of isomer ratios can be used in accordance with the present invention. For example, when only two isomers are combined, mixtures containing 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0 isomer ratios are all contemplated by the present invention. Those skilled in the art will readily recognize that similar ratios are contemplated for more complex isomer mixtures.

[0163] The present invention also includes isotopically labeled compounds that are identical to the compounds disclosed herein except for the fact that one or more atoms have been replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, e.g., 2 H, 3H, 13 C. 11 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F and 36 The compounds of the present invention or their enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts or solvates that contain the above isotopes and / or other isotopes of other atoms are included within the scope of the present invention. Certain isotopically labeled compounds of the present invention, for example, 3 H and 14 Those incorporating radioactive isotopes such as 1C are useful in drug and / or substrate tissue distribution assays. 3 H and carbon-14, i.e., 14 C isotopes are particularly preferred due to their ease of preparation and detectability. Additionally, deuterium, i.e., 2 Substitution with heavy isotopes such as H can offer therapeutic advantages due to greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements, and therefore may be preferable in certain circumstances. Isotopically labeled compounds can generally be prepared by performing the methods described in the schemes and / or examples below, replacing non-isotopically labeled reactants with readily available isotopically labeled reactants.

[0164] For example, if a specific enantiomer of a compound of this invention is desired, it may be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, separating the resulting diastereomeric mixture, and cleaving the auxiliary group to give the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group such as amino, or an acidic functional group such as carboxyl, a diastereomeric salt may be formed with a suitable optically active acid or base, followed by separation of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and recovery of the pure enantiomer.

[0165] It is recognized that the compounds described herein may be substituted with numerous substituents or functional moieties. In general, the term "substituted," whether preceded or followed by the term "optionally" and the substituents included in the formulae of the invention, refers to the replacement of a hydrogen radical in a structure with the radical of a specified substituent. When one or more positions in a structure may be substituted with more than one substituent selected from a specified group, the substituents may be the same or different at all positions. As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, permissible substituents include cyclic and annular, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. For purposes of this invention, heteroatoms, such as nitrogen, may have hydrogen substituents that satisfy the valence of the heteroatom and / or any permissible substituent of organic compounds described herein. Furthermore, it is not intended that the present invention be limited in any manner by the permissible substituents of organic compounds. Combinations of substituents and variables envisioned by this invention are preferably those that result in the formation of stable compounds useful, for example, in the treatment of proliferative disorders. As used herein, the term "stable" preferably refers to a compound that is stable enough to allow for manufacture and maintains its integrity for a sufficient period of time to be detected, preferably for a sufficient period of time to be useful for the purposes detailed herein.

[0166] As used herein, the terms "cancer" and, equivalently, "tumor" refer to a condition in which abnormally replicating cells of host origin are present in detectable amounts in a subject. Cancer can be malignant or non-malignant. Cancers or tumors include, but are not limited to, adult T-cell leukemia / lymphoma (including those caused by human T-cell lymphotropic virus 1 (HTLV-1)), bile duct cancer; brain cancer; breast cancer; cervical cancer; choriocarcinoma; colon cancer; endometrial cancer; esophageal cancer; gastric (corpus) cancer; intraepithelial neoplasia; leukemia; lymphoma; liver cancer; lung cancer (e.g., small cell and non-small cell); melanoma; neuroblastoma; oral cancer; ovarian cancer; pancreatic cancer; prostate cancer; rectal cancer; renal (kidney) cancer; sarcoma; skin cancer; testicular cancer; thyroid cancer; and other carcinomas and sarcomas. As used herein, the term "lymphoma" refers to a cancer of the lymphatic system or blood cancer that develops from lymphocytes. Cancer can be primary or metastatic. Diseases other than cancer can be associated with mutational alterations in components of the Ras signaling pathway, and the compounds disclosed herein can be used to treat these non-cancer diseases, including neurofibromatosis, Leopard syndrome, Noonan syndrome, Regius syndrome, Costello syndrome, cardio-facio-cutaneous syndrome, hereditary gingival fibromatosis type 1, autoimmune lymphoproliferative syndrome, and capillary malformation-arteriovenous malformation.

[0167] As used herein, "effective amount" refers to any amount necessary or sufficient to achieve or promote a desired outcome. In some cases, an effective amount is a therapeutically effective amount. A therapeutically effective amount is any amount necessary or sufficient to achieve or promote a desired biological response in a subject. The effective amount for a particular application may vary depending on factors such as the disease or condition being treated, the particular drug being administered, the size of the subject, or the severity of the disease or condition. Those skilled in the art can empirically determine the effective amount of a particular drug without the need for undue experimentation.

[0168] As used herein, the term "subject" refers to a vertebrate. In some embodiments, the subject is a mammal or mammalian species. In some embodiments, the subject is a human. In other embodiments, the subject is a non-human vertebrate, including, but not limited to, non-human primates, laboratory animals, livestock, racehorses, domestic animals, and non-domestic animals.

[0169] As used herein, the term "immune cells" refers to cells of the innate and adaptive immune systems, including, but not limited to, neutrophils, eosinophils, basophils, glial cells (e.g., astrocytes, microglia, and oligodendrocytes), monocytes, macrophages, dendritic cells, B cells, T cells, and lymphocytes, including NK cells.

[0170] As used herein, "conventional T cells" are T lymphocytes that express an αβ T cell receptor ("TCR") and the co-receptors CD4 or CD8. Conventional T cells are present in peripheral blood, lymph nodes, and tissues. See Roberts and Girardi, "Conventional and Unconventional T Cells," Clinical and Basic Immunodermatology, pp. 85-104, (Gaspari and Tyring (ed.)), Springer London (2008), incorporated herein by reference in its entirety. As used herein, "non-conventional T cells" are lymphocytes that express a γδ TCR and may generally reside in epithelial environments such as the skin, gastrointestinal tract, or genitourinary tract. Another subset of non-conventional T cells is invariant natural killer T ("NKT") cells, which have the phenotype and functional capabilities of conventional T cells and the properties of natural killer cells (e.g., cytolytic activity). See ibid. As used herein, regulatory T cells ("Tregs") are a subpopulation of T cells that regulate the immune system, maintain tolerance to self-antigens, prevent autoimmune disease, and otherwise suppress the immunostimulatory or activation responses of other cells. Tregs come in many forms, the best understood of which are those that express CD4, CD25, and Foxp3. As used herein, "natural Tregs" or "nTregs" refer to Tregs or cells that develop in the thymus. As used herein, "inducible Tregs" or "iTregs" refer to Tregs or cells that develop outside the thymus from mature CD4+ conventional T cells.

[0171] The "activity" of Akt3 refers to the biological function of the Akt3 protein. Biological activity can be increased or decreased by increasing or decreasing the basal level activity of the protein, increasing or decreasing the basal level avidity of the protein, the amount of the protein, the ratio of Akt3 to one or more other Akt isoforms (e.g., Akt1 or Akt2) proteins, increasing or decreasing the expression level of the protein (including increasing or decreasing Akt3 mRNA expression), or a combination thereof. For example, a bioavailable Akt3 protein is a protein that has kinase activity and can bind to and phosphorylate Akt3 substrates. A non-bioavailable Akt3 protein is an Akt3 protein that is mislocalized or cannot bind to and phosphorylate Akt substrates.

[0172] In some embodiments, the disclosed compounds selectively modulate Akt3 relative to Akt1 and Akt2. In some embodiments, none of the disclosed compounds modulates Akt1 and Akt2 to a statistically significant extent. In other embodiments, modulation of Akt3 by the disclosed compounds is about 5-fold, 10-fold, 15-fold, 50-fold, 100-fold, 1000-fold, or 5000-fold greater than modulation of Akt1 and / or Akt2.

[0173] As used herein, the term "peptide" or "polypeptide" refers to an amino acid chain of any length, regardless of modification (e.g., phosphorylation or glycosylation). The term includes proteins and fragments thereof. Polypeptides are "heterologous," i.e., "exogenous," meaning foreign to the host cell in which they are utilized, such as human polypeptides produced by bacterial cells. Polypeptides are described herein as amino acid residue sequences. These sequences are written from left to right, from amino terminus to carboxy terminus. According to standard nomenclature, amino acid residue sequences are designated by the following three-letter or single-letter codes: alanine (Ala, A), arginine (Arg, R), asparagine (Asn, N), aspartic acid (Asp, D), cysteine ​​(Cys, C), glutamine (Gln, Q), glutamic acid (Glu, E), glycine (Gly, G), histidine (His, H), isoleucine (Ile, I), leucine (Leu, L), lysine (Lys, K), methionine (Met, M), phenylalanine (Phe, F), proline (Pro, P), serine (Ser, S), threonine (Thr, T), tryptophan (Trp, W), tyrosine (Tyr, Y), and valine (Val, V).

[0174] The term "stimulate expression" means to affect expression, for example, to induce expression or activity or to induce increased / greater expression or activity relative to a normal, healthy control.

[0175] The terms "immunostimulatory response," "activating immune response," and "immunostimulatory response" refer to responses that initiate, induce, enhance, or increase the activation of innate or adaptive immunity, or that facilitate its activation. Such immune responses refer, for example, to the development of a beneficial humoral (antibody-mediated) and / or cellular (antigen-specific T cells or their secretory products-mediated) response to a peptide in a recipient patient. Such responses can be active responses induced by administration of an immunogen or passive responses induced by administration of antibodies or sensitized T cells. Cellular immune responses are elicited by the presentation of polypeptide epitopes in association with class I or class II major histocompatibility complex ("MHC") molecules to activate antigen-specific CD4+ T helper cells and / or CD8+ cytotoxic T cells. Responses can also include activation of monocytes, macrophages, NK cells, basophils, dendritic cells, astrocytes, microglial cells, eosinophils, or the activation or recruitment of neutrophils or other components of innate immunity. The presence of a cell-mediated immunological response can be determined by proliferation assays (CD4+ T cells) or cytotoxic T lymphocyte ("CTL") assays. The relative contributions of humoral and cellular responses to the protective or therapeutic effect of an immunogen can be distinguished by separately isolating antibodies and T cells from an immunized syngeneic animal and measuring the protective or therapeutic effect in a second subject.

[0176] The terms "suppressive immune response" and "immunosuppressive response" refer to a response that reduces or prevents the activation or efficiency of innate or adaptive immunity.

[0177] The term "immune tolerance" refers to any mechanism that prevents, suppresses, or shifts a potentially harmful immune response toward a non-harmful immune response (see Bach, et al., N. Eng. J. Med., 347:911-920 (2002)).

[0178] The term "immunogenic agent" or "immunogen" refers to an agent that is capable of inducing an immunological response against itself upon administration to a mammal, optionally in combination with an adjuvant.

[0179] compound In some embodiments, compounds of Formula Ia, Ib, or Ic are described as Akt3 modulators. Applicants have surprisingly discovered that the compounds disclosed herein modulate Akt3 activity, e.g., activate or inhibit Akt3 activity and / or downstream events, depending on their structure and substitution.

[0180] In some embodiments, a compound of formula Ia, Ib, or Ic [ka] or a pharmaceutically acceptable salt thereof, where: [ka] teeth [ka] and X1, X2, X3, X4, X5, X6, X7, X8 and X9 are independently at each occurrence CR1 or N; R1 is H, D, halogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) haloalkenyl, (C2-C6) alkynyl, (C2-C6) haloalkynyl, (C3-C7) cycloalkyl, (C4-C 10 )bicycloalkyl, (C3-C7)heterocycloalkyl, (C4-C 10 )heterobicycloalkyl, (C4-C 10 ) Heterospiroalkyl, halogenated (C3-C7)heterocycloalkyl, aryl, heteroaryl, -OR a , -SR a , -N(R a )2, -COR a , -CO2R a , CON(R a )2, -CN, -NC, NO2, N3, -SO2R a , -SO2N(R a )2, -N(R a )SO2R a , [ka] and optionally one or more of (C1-C6) alkyl, halogenated (C1-C6) alkyl, -SO2R a or -SO2N(R a ) 2 substituted partially saturated bicyclic heteroaryl; wherein R1 is (C3-C7)cycloalkyl, (C4-C 10 )bicycloalkyl, (C3-C7)heterocycloalkyl, (C4-C 10 )heterobicycloalkyl, (C4-C 10 ) Heterospiroalkyl, aryl and heteroaryl each optionally include one or more of (C1-C6) alkyl, halogenated (C1-C6) alkyl, halogen, -OR a , -CN or -N(R a )2 is substituted; n is an integer from 0 to 4 depending on the valence; Q is C(R a )2, O, NR a , N(C=O)R a or NSO2R a and; Y1, Y2, Y3, Y4 and Y5 are each independently N or CR2, depending on valence; R2 is H, D, halogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) haloalkenyl, (C2-C6) alkynyl, (C2-C6) haloalkynyl, (C3-C7) cycloalkyl, (C4-C 10 )bicycloalkyl, (C3-C7)heterocycloalkyl, (C4-C 10 )heterobicycloalkyl, (C4-C 10 ) Heterospiroalkyl, halogenated (C3-C7)heterocycloalkyl, aryl, heteroaryl, -OR a , -SR a , -N(R a )2, -COR a , -CO2R a , CON(R a )2, -CN, -NC, NO2, N3, -SO2Ra , -SO2N(R a )2, -N(R a )SO2R a , [ka] selected from the group consisting of: -EG- is -(C=O)NR x -, -NR x (C=O)-, -N(R x )(C=O)N(R x )-, -O(C=O)N(R x )-, -N(R x )(C=O)O-, -SO2NR x -, -NR x SO2- or [ka] where R x is independently at each occurrence H, (C-C)alkyl, (C-C)cycloalkyl, aryl, or heteroaryl; or R x and Y3, R x and Y4, R x and Z1 or R x and Z4 together form an optionally substituted 5- to 6-membered heterocycle; W1, W2, W3, W4 and W5 are each independently CR6, N or NR6, depending on the valence available; R6, independently at each occurrence, is selected from the group consisting of H, halogen, (C1-C6) alkyl, and (C1-C6) haloalkyl; T is independently in each occurrence O, N, or NR depending on the valence. a , N(C=O)R a , NC(R b )2OP(=O)(OR b )2 or NSO2R a and; U in each occurrence independently represents O, N, or NR depending on the valence. a , N(C=O)R a , NC(Rb )2OP(=O)(OR b )2 or NSO2R a and; R b is independently at each occurrence H or (C-C) alkyl; Z1, Z2, Z3, Z4 and Z5 are each independently N or CR3 where valence allows; R3 is H, D, halogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) haloalkenyl, (C2-C6) alkynyl, (C2-C6) haloalkynyl, (C3-C7) cycloalkyl, (C4-C 10 )bicycloalkyl, (C3-C7)heterocycloalkyl, (C4-C 10 )heterobicycloalkyl, (C4-C 10 ) Heterospiroalkyl, halogenated (C3-C7)heterocycloalkyl, aryl, heteroaryl, -OR a , -SR a , -N(R a )2, -COR a , -CO2R a , CON(R a )2, -CN, -NC, NO2, N3, -SO2R a , -SO2N(R a )2, -N(R a )SO2R a , [ka] selected from the group consisting of: V is absent, C(R a )2, NR a , N(C=O)R a , NSO2R a or O; R4 is (C1-C6) alkyl, (C3-C7) cycloalkyl, (C4-C 10 )bicycloalkyl, (C3-C7)heterocycloalkyl, (C4-C 10 )heterobicycloalkyl, (C4-C 10) selected from the group consisting of heterospiroalkyl, aryl, and heteroaryl, each optionally substituted with one or more R5; or alternatively, V and R4 together are (C3-C7)heterocycloalkyl or (C4-C 10 ) forming a heterospiroalkyl; R5, independently at each occurrence, is H, halogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) haloalkenyl, (C2-C6) alkynyl, (C2-C6) haloalkynyl, (C3-C7) cycloalkyl, (C4-C 10 )bicycloalkyl, (C3-C7)heterocycloalkyl, (C4-C 10 )heterobicycloalkyl, (C4-C 10 ) Heterospiroalkyl, halogenated (C3-C7)heterocycloalkyl, aryl, heteroaryl, -OR a , -SR a , -N(R a )2, -COR a , -CO2R a , CON(R a )2, -CN, -NC, NO2, N3, -SO2R a , -SO2N(R a )2, -N(R a )SO2R a , N(R a )COR a , [ka] selected from the group consisting of: R a is independently at each occurrence H, (C-C) alkyl, (C-C) alkenyl, (C-C) cycloalkyl, aryl, or heteroaryl, or two R a together form a 4- to 6-membered ring optionally substituted with halogen or (C1-C6) alkyl.

[0181] In one embodiment, [ka] teeth [ka] In one embodiment, [ka] teeth [ka] In one embodiment, [ka] teeth [ka] is.

[0182] In some embodiments, Q is C(R a )2, O or NR a In some embodiments, Q is O. In some embodiments, Q is NR a In some embodiments, Q is NH. In some embodiments, Q is NCH3 or NCH2CH3. In some embodiments, Q is N(C=O)R a or NSO2R a In some embodiments, Q is N(C=O)H. In some embodiments, Q is N(C=O)CH3 or N(C=O)CH2CH3. In some embodiments, Q is NSO2H. In some embodiments, Q is NSO2CH3 or NSO2CH2CH3.

[0183] In some embodiments, n is 0, 1, 2, 3, or 4. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0184] In one embodiment, [ka] teeth [ka] In some embodiments, X2, X3, and X4 are each independently CR1 or N. In some embodiments, X2, X3, and X4 are CR1. In some embodiments, X2, X3, and X4 are CH. In some embodiments, one of X2, X3, and X4 is N, and the remaining are CR1. In some embodiments, one of X2, X3, and X4 is N, and the remaining are CH. In some embodiments, two of X2, X3, and X4 are N, and the remaining are CR1. In some embodiments, two of X2, X3, and X4 are N, and the remaining are CH.

[0185] In certain embodiments, the structural moiety [ka] teeth [ka] It has the following structure.

[0186] In certain embodiments, the structural moiety [ka] teeth [ka] It has the following structure.

[0187] In certain embodiments, the structural moiety [ka] teeth [ka] It has the following structure.

[0188] In some embodiments, X1, X2, X3, X4, X5, X6, and X7 are each independently CR1 or N. In some embodiments, X1, X2, X3, X4, X5, X6, and X7 are CR1. In some embodiments, X1, X2, X3, X4, X5, X6, and X7 are each independently CH or CCH3. In some embodiments, one of X1, X2, X3, X4, X5, X6, and X7 is N, and the rest are CR1. In some embodiments, one of X1, X2, X3, X4, X5, X6, and X7 is N, and the rest are each independently CH or CCH3. In some embodiments, two of X1, X2, X3, X4, X5, X6, and X7 are N, and the rest are CR1. In some embodiments, two of X1, X2, X3, X4, X5, X6, and X7 are N, and the remaining are each independently CH or CCH3. In some embodiments, three of X1, X2, X3, X4, X5, X6, and X7 are N, and the remaining are CR1. In some embodiments, three of X1, X2, X3, X4, X5, X6, and X7 are N, and the remaining are each independently CH or CCH3. In some embodiments, four of X1, X2, X3, X4, X5, X6, and X7 are N, and the remaining are CR1. In some embodiments, four of X1, X2, X3, X4, X5, X6, and X7 are N, and the remaining are each independently CH or CCH3. In some embodiments, X2 is N, X7 is CR1, and X1, X3, X4, X5, and X6 are each independently CH or CCH3. In some embodiments, X2 is N, X7 is CR1, X3 is CCH3, and X1, X4, X5, and X6 are CH. In some embodiments, X2 and X7 are N, and X1, X3, X4, X5, and X6 are CR1. In some embodiments, X2 and X7 are N, and X1, X3, X4, X5, and X6 are each independently CH or CCH3.

[0189] In some embodiments, X2, X3, X4, X8, and X9 are each independently CR1 or N. In some embodiments, X2, X3, X4, X8, and X9 are each CR1. In some embodiments, X2, X3, X4, X8, and X9 are each independently CH or CCH3. In some embodiments, one of X2, X3, X4, X8, and X9 is N, and the remaining are CR1. In some embodiments, one of X2, X3, X4, X8, and X9 is N, and the remaining are each independently CH or CCH3. In some embodiments, two of X2, X3, X4, X8, and X9 are N, and the remaining are CR1. In some embodiments, two of X2, X3, X4, X8, and X9 are N, and the remaining are each independently CH or CCH3. In some embodiments, three of X2, X3, X4, X8, and X9 are N, and the remaining are CR1. In some embodiments, three of X2, X3, X4, X8, and X9 are N, and the remaining are each independently CH or CCH3. In some embodiments, four of X2, X3, X4, X8, and X9 are N, and one is CR1. In some embodiments, four of X2, X3, X4, X8, and X9 are N, and one is CH or CCH3.

[0190] In certain embodiments, the structural moiety [ka] teeth [ka] It has the following structure.

[0191] In certain embodiments, the structural moiety [ka] teeth [ka] In some embodiments, Q is O. In some embodiments, Q is NR a , N(C=O)R aor NSO2R a In some embodiments, Q is NH. In some embodiments, Q is NCH3 or NCH2CH3.

[0192] In certain embodiments, the structural moiety [ka] teeth [ka] In some embodiments, the structural moiety [ka] teeth [ka] In some embodiments, Q is O. In some embodiments, Q is NR a , N(C=O)R a or NSO2R a In some embodiments, Q is NH. In some embodiments, Q is NCH3 or NCH2CH3.

[0193] In certain embodiments, the structural moiety [ka] teeth [ka] It has the following structure.

[0194] In certain embodiments, the structural moiety [ka] teeth [ka] In some embodiments, the structural moiety [ka] teeth [ka] In some embodiments, the structural moiety [ka] teeth [ka] In some embodiments, the structural moiety [ka] teeth [ka] In one embodiment, the partial structure [ka] teeth [ka] It has the following structure.

[0195] In certain embodiments, the structural moiety [ka] teeth [ka] In some embodiments, the structural moiety [ka] teeth [ka] In some embodiments, Q is O. In some embodiments, Q is NR a , N(C=O)R a or NSO2R a In some embodiments, Q is NH. In some embodiments, Q is NCH3 or NCH2CH3.

[0196] In certain embodiments, R1, at each occurrence, is independently H, D, halogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)haloalkenyl, (C2-C6)alkynyl, (C2-C6)haloalkynyl, (C3-C7)cycloalkyl, (C4-C 10 )bicycloalkyl, (C3-C7)heterocycloalkyl, (C4-C 10 ) Heterobicycloalkyl, aryl, heteroaryl, -OR a , -N(R a )2, -COR a , -CO2R a , CON(R a )2, -CN, -NC, NO2, N3, -SO2R a , -SO2N(R a )2 and -N(R a )SO2R a wherein (C3-C7)cycloalkyl, (C4-C 10 )bicycloalkyl, (C3-C7)heterocycloalkyl, (C4-C 10 )heterobicycloalkyl, (C4-C 10 ) heterospiroalkyl, aryl, and heteroaryl are each optionally substituted with one or more (C1-C6) alkyl. In some embodiments, R1, at each occurrence, is independently selected from (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) haloalkenyl, (C2-C6) alkynyl, (C2-C6) haloalkynyl, (C3-C7) cycloalkyl, (C4-C 10 )bicycloalkyl, (C3-C7)heterocycloalkyl and (C4-C 10)heterobicycloalkyl; wherein (C3-C7)cycloalkyl, (C4-C 10 )bicycloalkyl, (C3-C7)heterocycloalkyl and (C4-C 10 )heterobicycloalkyl is optionally substituted with one or more (C1-C6)alkyl. In certain embodiments, R1 is independently selected at each occurrence from the group consisting of aryl and heteroaryl; 10 ) heterospiroalkyl, aryl, and heteroaryl are each optionally substituted with one or more (C1-C6) alkyl. In some embodiments, R1 is independently at each occurrence -OR a , -SR a , -N(R a )2, -COR a , -CO2R a , CON(R a )2, -CN, -NC, NO2, N3, -SO2R a , -SO2N(R a )2 and -N(R a )SO2R a In certain embodiments, R is independently at each occurrence selected from the group consisting of [ka] In some embodiments, R is independently at each occurrence selected from the group consisting of H, D, halogen, OR a , N(R a )2, (C1-C6) alkyl, (C3-C7) heterocycloalkyl, (C4-C 10 ) heterospiroalkyl, halogenated (C3-C7) heterocycloalkyl, (C1-C6) alkynyl, aryl, (C4-C 10 ) Bicycloalkyl, -CN, -NC, N3, NO2, COR a , CO2R a , CON(R a )2, -SO2R a or -SO2N(R a )2; where (C3-C7)heterocycloalkyl, (C4-C 10 ) heterospiroalkyl, aryl and (C4-C10 )bicycloalkyl is optionally substituted with one or more (C1-C6)alkyl. In some embodiments, R1, at each occurrence, is independently selected from H, D, halogen, (C1-C6)alkyl, (C3-C7)heterocycloalkyl, (C4-C 10 )heterospiroalkyl, halogenated (C3-C7)heterocycloalkyl, N(R a )2 or -CN; where (C3-C7)heterocycloalkyl and (C4-C 10 )heterospiroalkyl is optionally substituted with one or more (C1-C6)alkyl. In some embodiments, at least one of R1 is (C4-C 10 )heterospiroalkyl. In some embodiments, at least one R is a halogenated (C3-C7)heterocycloalkyl. In some embodiments, R is independently at each occurrence H, (C1-C6)alkyl, (C1-C6)alkynyl, aryl, (C4-C 10 ) Bicycloalkyl, -SO2R a or -SO2N(R a )2; wherein aryl and (C4-C 10 )bicycloalkyl are each optionally substituted with one or more (C1-C6)alkyl. In some embodiments, at least one R1 is optionally substituted with one or more (C1-C6)alkyl (C4-C 10 )heterospiroalkyl. In some embodiments, at least one R is a halogenated (C3-C7)heterocycloalkyl optionally substituted with one or more (C1-C6)alkyl. In some embodiments, R is independently at each occurrence H, D, F, Cl, Br, CH3, OCH3, NH2, NHCH3, N(CH3)2, [ka] where R a In some embodiments, R' is H or (C1-C6) alkyl. In some embodiments, R1 is independently at each occurrence H, D, F, CH3, N(CH3)2, [ka] where R a In certain embodiments, R is independently at each occurrence H or (C-C) alkyl. [ka] is.

[0197] In some embodiments, R is (C-C)cycloalkyl, (C-C 10 )bicycloalkyl, (C3-C7)heterocycloalkyl, (C4-C 10 )heterobicycloalkyl, (C4-C 10 ) Heterospiroalkyl, aryl and heteroaryl each optionally include one or more halogens, -OR a , -CN or -N(R a )2.

[0198] In certain embodiments, at least one R is optionally one or more of (C-C) alkyl, halogenated (C-C) alkyl, -SOR a or -SO2N(R a In some embodiments, at least one of R is a partially saturated bicyclic heteroaryl substituted with 2. [ka] In one embodiment, [ka] teeth [ka] is.

[0199] In some embodiments, at least one of R1 is H, D, or halogen. In some embodiments, at least one of R1 is H. In some embodiments, at least one of R1 is D. In some embodiments, at least one of R1 is F. In some embodiments, at least one of R1 is CH3. In some embodiments, at least one of R1 is OCH3. In some embodiments, at least one of R1 is NH2. In some embodiments, at least one of R1 is NHCH3. In some embodiments, at least one of R1 is N(CH3)2. In some embodiments, at least one of R1 is F. In some embodiments, at least one of R1 is [ka] In some embodiments, at least one of R1 is [ka] In some embodiments, at least one of R1 is [ka] In some embodiments, at least one of R1 is [ka] In some embodiments, at least one of R1 is [ka] In some embodiments, at least one of R1 is [ka] In some embodiments, at least one of R1 is [ka] In some embodiments, at least one of R1 is [ka] where R a ' is H or (C1-C6) alkyl. In some embodiments, at least one of R1 is [ka] In some embodiments, at least one of R1 is [ka] In some embodiments, at least one of R1 is [ka] In some embodiments, at least one of R1 is [ka] In some embodiments, at least one of R1 is [ka] In some embodiments, at least one of R1 is [ka] In some embodiments, at least one of R1 is [ka] In some embodiments, at least one of R1 is [ka] In some embodiments, at least one of R1 is [ka] In some embodiments, at least one of R1 is [ka] In some embodiments, R1 is [ka] In some embodiments, at least one of R1 is [ka] In some embodiments, at least one of R1 is [ka] In some embodiments, at least one of R1 is [ka] where R a ' is H or (C1-C6) alkyl. In some embodiments, at least one of R1 is [ka] In some embodiments, at least one of R1 is [ka] In some embodiments, at least one of R1 is [ka] In some embodiments, at least one of R1 is [ka] In some embodiments, at least one of R1 is [ka] In some embodiments, at least one of R1 is [ka] In some embodiments, at least one R is -CN. In some embodiments, at least one R is -NC. In some embodiments, at least one R is [ka] In some embodiments, at least one of R1 is [ka] In some embodiments, at least one of R1 is [ka] In some embodiments, at least one of R1 is [ka] In some embodiments, at least one of R1 is NO2. In some embodiments, at least one of R1 is N3. In some embodiments, at least one of R1 is [ka] In some embodiments, at least one of R1 is [ka] is.

[0200] In certain embodiments, the structural moiety [ka] teeth [ka] [ka] [ka] In some embodiments, the structural moiety [ka] teeth [ka] In one embodiment, the partial structure [ka] teeth [ka] In some embodiments, the structural moiety [ka] teeth [ka] In some embodiments, the structural moiety [ka] teeth [ka] In some embodiments, the structural moiety [ka] teeth [ka] In some embodiments, the structural moiety [ka] teeth [ka] In some embodiments, the structural moiety [ka] teeth [ka] In some embodiments, the structural moiety [ka] teeth [ka] In some embodiments, the structural moiety [ka] teeth [ka] In some embodiments, the structural moiety [ka] teeth [ka] In some embodiments, the structural moiety [ka] teeth [ka] It has the following structure.

[0201] In certain embodiments, the structural moiety [ka] teeth [ka] wherein Q is O or NH. In certain embodiments, the structural moiety [ka] teeth [ka] wherein Q is O or NH. In certain embodiments, the structural moiety [ka] teeth [ka] wherein Q is O or NH. In certain embodiments, the structural moiety [ka] teeth [ka] wherein Q is O or NH. In certain embodiments, the structural moiety [ka] teeth [ka] wherein Q is O or NH. In certain embodiments, the structural moiety [ka] teeth [ka] wherein Q is O or NH. In certain embodiments, the structural moiety [ka] teeth [ka] wherein Q is O or NH. In certain embodiments, the structural moiety [ka] teeth [ka] wherein Q is O or NH. In certain embodiments, the structural moiety [ka] teeth [ka] wherein Q is O or NH. In certain embodiments, the structural moiety [ka] teeth [ka] where Q is O or NH.

[0202] In certain embodiments, the structural moiety [ka] teeth [ka] wherein Q is O or NH and R is H, D, (C-C) alkyl, (C-C) heterocycloalkyl, halogenated (C-C) heterocycloalkyl, or halogen. [ka] teeth [ka] where Q is O or NH and R1 is H, D, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, F, Cl, or Br.

[0203] In certain embodiments, the structural moiety [ka] teeth [ka] wherein Q is O or NH. In certain embodiments, the structural moiety [ka] teeth [ka] wherein Q is O or NH. In certain embodiments, the structural moiety [ka] teeth [ka] wherein Q is O or NH. In certain embodiments, the structural moiety [ka] teeth [ka] where Q is O or NH.

[0204] In certain embodiments, the structural moiety [ka] teeth [ka] In some embodiments, the structural moiety [ka] teeth [ka] In some embodiments, the structural moiety [ka] teeth [ka] In some embodiments, the structural moiety [ka] teeth [ka] In some embodiments, the structural moiety [ka] teeth [ka] In some embodiments, the structural moiety [ka] teeth [ka] In certain embodiments, Q is O or NH.

[0205] In certain embodiments, the compound has the structure of Formula Ia.

[0206] In some embodiments, Y1, Y2, Y3, Y4, and Y5 are each independently CR2 or N. In some embodiments, Y1, Y2, Y3, Y4, and Y5 are each CR2. In some embodiments, Y1, Y2, Y3, Y4, and Y5 are each CH. In some embodiments, Y1, Y2, Y3, Y4, and Y5 are each N. In some embodiments, one of Y1, Y2, Y3, Y4, and Y5 is CR2, and the rest are N. In some embodiments, one of Y1, Y2, Y3, Y4, and Y5 is CH, and the rest are N. In some embodiments, two of Y1, Y2, Y3, Y4, and Y5 are CR2, and the rest are N. In some embodiments, two of Y1, Y2, Y3, Y4, and Y5 are CH, and the rest are N. In some embodiments, three of Y1, Y2, Y3, Y4, and Y5 are CR2 and two of Y1, Y2, Y3, Y4, and Y5 are N. In some embodiments, three of Y1, Y2, Y3, Y4, and Y5 are CH and two of Y1, Y2, Y3, Y4, and Y5 are N.

[0207] In certain embodiments, the structural moiety [ka] teeth [ka] In some embodiments, the structural moiety [ka] teeth [ka] It has the following structure.

[0208] In certain embodiments, R2, independently at each occurrence, is H, D, halogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)haloalkenyl, (C2-C6)alkynyl, (C2-C6)haloalkynyl, (C3-C7)cycloalkyl, (C4-C 10)bicycloalkyl, (C4-C 10 )heterobicycloalkyl, (C3-C7)heterocycloalkyl, (C4-C 10 ) Heterobicycloalkyl, aryl, heteroaryl, -OR a , -N(R a )2, -COR a , -CO2R a , CON(R a )2, -CN, -NC, NO2, N3, -SO2R a , -SO2N(R a )2 and -N(R a )SO2R a In certain embodiments, R2, independently at each occurrence, is selected from the group consisting of (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)haloalkenyl, (C2-C6)alkynyl, (C2-C6)haloalkynyl, (C3-C7)cycloalkyl, (C4-C 10 )bicycloalkyl, (C3-C7)heterocycloalkyl and (C4-C 10 In some embodiments, R2 is independently at each occurrence selected from the group consisting of aryl and heteroaryl. In some embodiments, R2 is independently at each occurrence -OR a , -SR a , -N(R a )2, -COR a , -CO2R a , CON(R a )2, -CN, -NC, NO2, N3, -SO2R a , -SO2N(R a )2 and -N(R a )SO2R a In certain embodiments, R2 is independently at each occurrence selected from the group consisting of [ka] In some embodiments, R2 is independently selected from the group consisting of H, D, halogen, OR a , N(R a)2, (C1-C6) alkyl, (C3-C7) heterocycloalkyl, (C1-C6) alkynyl, aryl, (C4-C 10 ) Bicycloalkyl, -CN, -NC, N3, NO2, COR a , CO2R a , CON(R a )2, -SO2R a or -SO2N(R a In certain embodiments, R2 is independently at each occurrence H, D, halogen, (C1-C6)alkyl, (C3-C7)heterocycloalkyl, N(R a )2 or -CN. In certain embodiments, R2 is independently at each occurrence (C4-C 10 )heterospiroalkyl, halogenated (C3-C7)heterocycloalkyl, aryl, or heteroaryl. In certain embodiments, R2 is independently at each occurrence H, (C1-C6)alkyl, (C1-C6)alkynyl, aryl, (C4-C 10 ) Bicycloalkyl, -SO2R a or -SO2N(R a In certain embodiments, R2 is independently at each occurrence H, D, F, Cl, Br, CH3, OCH3, NH2, N(CH3)2, [ka] In some embodiments, R2 is independently at each occurrence H, D, F, CH3, N(CH3)2, [ka] is.

[0209] In some embodiments, at least one of R2 is H, D, or halogen. In some embodiments, at least one of R2 is H. In some embodiments, at least one of R2 is D. In some embodiments, at least one of R2 is F. In some embodiments, at least one of R2 is CH3. In some embodiments, at least one of R2 is OCH3. In some embodiments, at least one of R2 is NH2. In some embodiments, at least one of R2 is N(CH3)2. In some embodiments, at least one of R2 is [ka] In some embodiments, at least one of R2 is [ka] In some embodiments, at least one of R2 is [ka] In some embodiments, at least one of R2 is [ka] In some embodiments, at least one of R2 is [ka] In some embodiments, at least one of R2 is [ka] In some embodiments, at least one of R2 is [ka] In some embodiments, at least one of R2 is [ka] where Ra ' is H or (C1-C6) alkyl. In some embodiments, at least one of R2 is [ka] In some embodiments, at least one of R2 is [ka] In some embodiments, at least one of R2 is [ka] In some embodiments, at least one of R2 is [ka] In some embodiments, at least one of R2 is [ka] where R a ' is H or (C1-C6) alkyl. In some embodiments, at least one of R2 is [ka] In some embodiments, at least one of R2 is [ka] In some embodiments, at least one of R2 is [ka] In some embodiments, at least one of R2 is [ka] In some embodiments, at least one of R2 is [ka] In some embodiments, at least one of R2 is [ka] In some embodiments, at least one of R2 is -CN. In some embodiments, at least one of R2 is -NC. In some embodiments, at least one of R2 is [ka] In some embodiments, at least one of R2 is [ka] In some embodiments, at least one of R2 is [ka] In some embodiments, at least one of R2 is [ka] In some embodiments, at least one of R2 is NO2. In some embodiments, at least one of R2 is N3. In some embodiments, at least one of R2 is [ka] In some embodiments, at least one of R2 is [ka] is.

[0210] In certain embodiments, R2 is independently at each occurrence H, halogen, (C1-C6) alkyl, (C1-C6) haloalkyl, -N(R a )2, NO2 and -OR aIn some embodiments, R2 is, independently at each occurrence, H, halogen, CH3, CF3, OH, NH2, -NHCH3, or -N(CH3)2. In some embodiments, at least one R2 is H. In some embodiments, at least one R2 is (C1-C6) alkyl. In some embodiments, at least one R2 is -N(R a )2, NO2 or -OR a In some embodiments, at least one of R2 is H, CH3, OH, NH2, or halogen. In some embodiments, at least one of R2 is H. In some embodiments, at least one of R2 is CF3. In some embodiments, R2 is H or CH3.

[0211] In certain embodiments, the structural moiety [ka] teeth [ka] It has the following structure.

[0212] In some embodiments, Z1, Z2, Z3, Z4, and Z5 are each independently CR3 or N. In some embodiments, Z1, Z2, Z3, Z4, and Z5 are each independently CR3. In some embodiments, Z1, Z2, Z3, Z4, and Z5 are each independently CH. In some embodiments, Z1, Z2, Z3, Z4, and Z5 are each N. In some embodiments, one of Z1, Z2, Z3, Z4, and Z5 is CR3, and the rest are N. In some embodiments, one of Z1, Z2, Z3, Z4, and Z5 is CH, and the rest are N. In some embodiments, two of Z1, Z2, Z3, Z4, and Z5 are CR3, and the rest are N. In some embodiments, two of Z1, Z2, Z3, Z4, and Z5 are CH, and the rest are N. In some embodiments, three of Z1, Z2, Z3, Z4, and Z5 are CR3 and two are N. In some embodiments, three of Z1, Z2, Z3, Z4, and Z5 are CH and two are N. In some embodiments, Z4 is N and Z1, Z2, Z3, and Z5 are CR3.

[0213] In certain embodiments, the structural moiety [ka] teeth [ka] In some embodiments, the structural moiety [ka] teeth [ka] It has the following structure.

[0214] In certain embodiments, the structural moiety [ka] teeth [ka] It has the following structure.

[0215] In certain embodiments, the structural moiety [ka] teeth [ka] In some embodiments, the structural moiety [ka] teeth [ka] In some embodiments, the structural moiety [ka] teeth [ka] In some embodiments, the structural moiety [ka] teeth [ka] In some embodiments, the structural moiety [ka] teeth [ka] In some embodiments, the structural moiety [ka] teeth [ka] In some embodiments, the structural moiety [ka] teeth [ka] In these embodiments, the structural moiety [ka] teeth [ka] It has the following structure.

[0216] In some embodiments, R x is independently at each occurrence H, (C-C)alkyl, (C-C)cycloalkyl, aryl, or heteroaryl; or R x and Y3, R x and Y4, R x and Z1 or R x and Z4 together form an optionally substituted 5- to 6-membered heterocycle. x is independently at each occurrence H, (C1-C6) alkyl, (C3-C7) cycloalkyl, aryl, or heteroaryl. In certain embodiments, R x is independently at each occurrence H, CH, or CHCH. In certain embodiments, R x and Y4 together form an optionally substituted 5- to 6-membered heterocycle. x and Y3 together form an optionally substituted 5- to 6-membered heterocycle. x and Z1 together form an optionally substituted 5- to 6-membered heterocycle. x and Z4 together form an optionally substituted 5- to 6-membered heterocycle.

[0217] In certain embodiments, the structural moiety [ka] teeth [ka] It has the following structure.

[0218] In some embodiments, W1, W2, W3, W4, and W5 are each independently CR6, N, or NR6, depending on the valence available. In some embodiments, one of W1, W2, W3, W4, and W5 is N or NR6, and the remaining are C or CR6, depending on the valence available. In some embodiments, two of W1, W2, W3, W4, and W5 are N or NR6, and the remaining are C or CR6, depending on the valence available. In some embodiments, three of W1, W2, W3, W4, and W5 are N or NR6, and two are C or CR6, depending on the valence available. In some embodiments, one of W1, W2, W3, W4, and W5 is N, and the remaining are C or CR6, depending on the valence available. In some embodiments, two of W1, W2, W3, W4, and W5 are N, and the remaining are C or CR6, depending on the valence available. In some embodiments, three of W1, W2, W3, W4 and W5 are N and two are C or CR6 depending on valence.

[0219] In certain embodiments, R6 is independently at each occurrence selected from the group consisting of H, halogen, (C1-C6) alkyl, and (C1-C6) haloalkyl. In certain embodiments, R6 is independently at each occurrence selected from the group consisting of H, F, CH3, and CH2CH3.

[0220] In certain embodiments, the structural moiety [ka] teeth [ka] In some embodiments, the structural moiety [ka] teeth [ka] It has the following structure.

[0221] In certain embodiments, the structural moiety [ka] teeth [ka] In some embodiments, R3 is H, CH3, OH, halogen, or NH2. In some embodiments, R x is H, CH3 or CH2CH3.

[0222] In certain embodiments, the structural moiety [ka] teeth [ka] In some embodiments, the structural moiety [ka] teeth [ka] In some embodiments, the structural moiety [ka] teeth [ka] In these embodiments, m is independently 1 or 2 at each occurrence, and J is C(R y )2 and R y is independently at each occurrence H, (C1-C6)alkyl, OH, O(C1-C6)alkyl, or halogen. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, R y is independently at each occurrence H or (C-C) alkyl. In certain embodiments, R y is independently at each occurrence OH, O(C-C)alkyl, or halogen. In certain embodiments, R y is H in each case.

[0223] In certain embodiments, the structural moiety [ka] teeth [ka] In some embodiments, the structural moiety [ka] teeth [ka] In some embodiments, the structural moiety [ka] teeth [ka] In some embodiments, the structural moiety [ka] teeth [ka] In some embodiments, the structural moiety [ka] teeth [ka] In some embodiments, Y1, Y2, Y3, and Y4 are each independently N, CH, CCH3, or CF. In some embodiments, Y1, Y2, Y3, and Y4 are each independently N or CH.

[0224] In certain embodiments, the structural moiety [ka] teeth [ka] where m is independently in each occurrence 1 or 2 and J is C(R z )2 and R z is independently at each occurrence H, (C1-C6)alkyl, OH, O(C1-C6)alkyl, or halogen. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, R z is independently at each occurrence H or (C-C) alkyl. In certain embodiments, R z is independently at each occurrence OH, O(C-C)alkyl, or halogen. In certain embodiments, R z is H in each case.

[0225] In certain embodiments, the structural moiety [ka] teeth [ka] In some embodiments, the structural moiety [ka] teeth [ka] In some embodiments, the structural moiety [ka] teeth [ka] In some embodiments, Z1, Z2, Z3, and Z4 are each independently N, CH, CCH3, or CF. In some embodiments, Z1, Z2, Z3, and Z4 are each independently N or CH.

[0226] In certain embodiments, the compound has the structure of Formula Ib.

[0227] In some embodiments, T is N(C=O)R a or NSO2R a In some embodiments, T is N(C=O)Me or N(C=O)Et. In some embodiments, T is NSO2Me or NSO2Et. In some embodiments, T is O or NR a In some embodiments, T is O. In some embodiments, T is NR a In some embodiments, T is NH. In some embodiments, T is NCH3 or NCH2CH3. In some embodiments, T is NC(R b )2OP(=O)(OR b )2.

[0228] In some embodiments, U is N(C=O)R a or NSO2R a In some embodiments, U is N(C=O)Me or N(C=O)Et. In some embodiments, U is NSO2Me or NSO2Et. In some embodiments, U is O or NR a In some embodiments, U is O. In some embodiments, U is NR aIn some embodiments, U is NH. In some embodiments, U is NCH3 or NCH2CH3. In some embodiments, U is NC(R b )2OP(=O)(OR b )2.

[0229] In some embodiments, R b is independently at each occurrence H or (C-C) alkyl. In certain embodiments, R b is independently at each occurrence H, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, or tert-butyl. b is independently at each occurrence H or CH. In certain embodiments, R b is H in each case.

[0230] In certain embodiments, the structural moiety [ka] teeth [ka] where T and U are independently in each occurrence O, N, NR, or any of the valence-dependent a , N(C=O)R a , NC(R b )2OP(=O)(OR b )2 or NSO2R a is.

[0231] In certain embodiments, the structural moiety [ka] teeth [ka] It has the following structure.

[0232] In certain embodiments, the structural moiety [ka] teeth [ka] where R b is independently at each occurrence H or CH. In certain embodiments, the structural moiety [ka] teeth [ka] where R b is independently at each occurrence H or CH. In certain embodiments, the structural moiety [ka] teeth [ka] where R b is independently in each occurrence H or CH3.

[0233] In certain embodiments, the compound has the structure of Formula Ic.

[0234] In certain embodiments, the structural moiety [ka] teeth [ka] where T and U are independently in each occurrence O, N, NR, or any of the valence-dependent a , N(C=O)R a , NC(R b )2OP(=O)(OR b )2 or NSO2R a is.

[0235] In certain embodiments, the structural moiety [ka] teeth [ka] where R2 is H, CH3, OH, halogen, or NH2; and where R a is H, CH, or CHCH. In some embodiments, R is H, CH, OH, halogen, or NH. In some embodiments, R a is H, CH3 or CH2CH3.

[0236] In certain embodiments, the structural moiety [ka] teeth [ka] In some embodiments, the structural moiety [ka] teeth [ka] In some embodiments, the structural moiety [ka] teeth [ka] In one embodiment, R b is independently in each occurrence H or CH3.

[0237] In certain embodiments, R3, at each occurrence, is independently H, D, halogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)haloalkenyl, (C2-C6)alkynyl, (C2-C6)haloalkynyl, (C3-C7)cycloalkyl, (C4-C 10 )bicycloalkyl, (C3-C7)heterocycloalkyl, (C4-C 10 ) Heterobicycloalkyl, aryl, heteroaryl, -OR a , -N(R a )2, -COR a , -CO2R a , CON(R a )2, -CN, -NC, NO2, N3, -SO2R a , -SO2N(R a )2 and -N(R a )SO2R a In some embodiments, R3 is independently at each occurrence selected from the group consisting of (C4-C 10 )heterospiroalkyl, halogenated (C3-C7)heterocycloalkyl, aryl, or heteroaryl. In certain embodiments, R3 is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)haloalkenyl, (C2-C6)alkynyl, (C2-C6)haloalkynyl, (C3-C7)cycloalkyl, (C4-C 10 )bicycloalkyl, (C3-C7)heterocycloalkyl and (C4-C 10 In some embodiments, R3 is independently at each occurrence selected from the group consisting of aryl and heteroaryl. In some embodiments, R3 is independently at each occurrence -OR a , -SR a , -N(R a )2, -COR a , -CO2R a , CON(R a )2, -CN, -NC, NO2, N3, -SO2R a , -SO2N(R a )2 and -N(R a )SO2R aIn certain embodiments, R3 is independently at each occurrence selected from the group consisting of [ka] In some embodiments, R3 is independently selected from the group consisting of H, D, halogen, OR a , N(R a )2, (C1-C6) alkyl, (C3-C7) heterocycloalkyl, (C1-C6) alkynyl, aryl, (C4-C 10 ) Bicycloalkyl, -CN, -NC, N3, NO2, COR a , CO2R a , CON(R a )2, -SO2R a or -SO2N(R a In certain embodiments, R3 is independently at each occurrence H, D, halogen, (C1-C6)alkyl, (C3-C7)heterocycloalkyl, N(R a )2 or -CN. In certain embodiments, R3 is independently at each occurrence H, (C1-C6) alkyl, (C1-C6) alkynyl, aryl, (C4-C 10 ) Bicycloalkyl, -SO2R a or -SO2N(R a In certain embodiments, R3 is independently at each occurrence H, D, F, Cl, Br, CH3, OCH3, NH2, N(CH3)2, [ka] In some embodiments, R3 is independently at each occurrence H, D, F, CH3, N(CH3)2, [ka] is.

[0238] In some embodiments, at least one of R3 is H, D, or halogen. In some embodiments, at least one of R3 is H. In some embodiments, at least one of R3 is D. In some embodiments, at least one of R3 is F. In some embodiments, at least one of R3 is CH3. In some embodiments, at least one of R3 is OCH3. In some embodiments, at least one of R3 is NH2. In some embodiments, at least one of R3 is N(CH3)2. In some embodiments, at least one of R3 is [ka] In some embodiments, at least one of R3 is [ka] In some embodiments, at least one of R3 is [ka] In some embodiments, at least one of R3 is [ka] In some embodiments, at least one of R3 is [ka] In some embodiments, at least one of R3 is [ka] In some embodiments, at least one of R3 is [ka] In some embodiments, at least one of R3 is [ka] where Ra ' is H or (C1-C6) alkyl. In some embodiments, at least one of R3 is [ka] In some embodiments, at least one of R3 is [ka] In some embodiments, at least one of R3 is [ka] In some embodiments, at least one of R3 is [ka] In some embodiments, at least one of R3 is [ka] where R a ' is H or (C1-C6) alkyl. In some embodiments, at least one of R3 is [ka] In some embodiments, at least one of R3 is [ka] In some embodiments, at least one of R3 is [ka] In some embodiments, at least one of R3 is [ka] In some embodiments, at least one of R3 is [ka] In some embodiments, at least one of R3 is [ka] In some embodiments, at least one R is -CN. In some embodiments, at least one R is [ka] In some embodiments, at least one of R3 is [ka] In some embodiments, at least one of R3 is [ka] In some embodiments, at least one R is -NC. In some embodiments, at least one R is [ka] In some embodiments, at least one of R3 is NO2. In some embodiments, at least one of R3 is N3. In some embodiments, at least one of R3 is [ka] In some embodiments, at least one of R3 is [ka] is.

[0239] In certain embodiments, R3 is independently at each occurrence H, halogen, (C1-C6)alkyl, (C1-C6)haloalkyl, -N(R a )2, NO2 and -OR aIn some embodiments, at least one of R3 is H, CH3, OH, NH2, or halogen. In some embodiments, at least one of R3 is H or CH3. In some embodiments, at least one of R3 is OH or NH2. In some embodiments, at least one of R3 is halogen. In some embodiments, at least one of R3 is H. In some embodiments, at least one of R3 is CF3. In some embodiments, R3 is H or CH3.

[0240] In some embodiments, V is absent, O, or NR a In some embodiments, V is absent. In some embodiments, V is O. In some embodiments, V is NR a In some embodiments, V is NH. In some embodiments, V is NCH3 or NCH2CH3.

[0241] In some embodiments, V is N(C=O)R a or NSO2R a In some embodiments, V is N(C=O)H. In some embodiments, V is N(C=O)CH3 or N(C=O)CH2CH3. In some embodiments, V is NSO2H. In some embodiments, V is NSO2CH3 or NSO2CH2CH3.

[0242] In certain embodiments, the structural moiety [ka] teeth [ka] In some embodiments, the structural moiety [ka] teeth [ka] In some embodiments, the structural moiety [ka] teeth [ka] It has the following structure.

[0243] In certain embodiments, the structural moiety [ka] V and R4 are united (C4-C 10 ) forming a heterospiroalkyl.

[0244] In some embodiments, R4 is (C1-C6) alkyl, (C3-C7) cycloalkyl, (C4-C 10 )bicycloalkyl, (C3-C7)heterocycloalkyl, (C4-C 10 )heterobicycloalkyl, aryl, and heteroaryl, each optionally substituted with one or more R. In certain embodiments, R is substituted with 0, 1, 2, 3, 4, 5, or 6 R substituents, wherein each R is H, halogen, (C-C)alkyl, (C-C)haloalkyl, (C-C)alkenyl, (C-C)haloalkenyl, (C-C)alkynyl, (C-C)haloalkynyl, (C-C)cycloalkyl, (C-C 10 )bicycloalkyl, (C3-C7)heterocycloalkyl, (C4-C 10 ) Heterobicycloalkyl, aryl, heteroaryl, -OR a , -SR a , -N(R a )2, N(R a )COR a , -COR a , -CO2R a , CON(R a )2, -CN, -NC, NO2, N3, -SO2R a , -SO2N(Ra )2, -N(R a )SO2R a , [ka] In some embodiments, R5 is independently selected at each occurrence from the group consisting of (C4-C 10 )heterospiroalkyl, halogenated (C3-C7)heterocycloalkyl, aryl, or heteroaryl. In some embodiments, R4 is [ka] where: [ka] wherein R5 may be attached to any position of the bicycloalkyl or heterobicycloalkyl, including the bridgehead carbon, [ka] In one embodiment, R4 is [ka] In some embodiments, R4 is [ka] In some embodiments, R4 is [ka] In some embodiments, R4 is [ka] In some embodiments, R4 is [ka] In some embodiments, R4 is [ka] In some embodiments, R4 is [ka] In some embodiments, R4 is [ka] In some embodiments, m is an integer from 0 to 3. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0245] In certain embodiments, the structural moiety [ka] teeth [ka] In some embodiments, V has the structure: a )2, O, NR a , N(C=O)R a or NSO2R a In some embodiments, V' is CR a Or N.

[0246] In certain embodiments, R5, at each occurrence, is independently H, D, halogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)haloalkenyl, (C2-C6)alkynyl, (C2-C6)haloalkynyl, (C3-C7)cycloalkyl, (C4-C 10 )bicycloalkyl, (C3-C7)heterocycloalkyl, (C4-C 10 ) Heterobicycloalkyl, aryl, heteroaryl, -OR a , -N(R a )2, -COR a , -CO2R a , N(R a)COR a , CON(R a )2, -CN, -NC, NO2, N3, -SO2R a , -SO2N(R a )2 and -N(R a )SO2R a In certain embodiments, R5, at each occurrence, is independently selected from the group consisting of (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)haloalkenyl, (C2-C6)alkynyl, (C2-C6)haloalkynyl, (C3-C7)cycloalkyl, (C4-C 10 )bicycloalkyl, (C3-C7)heterocycloalkyl and (C4-C 10 In certain embodiments, R5 is independently at each occurrence selected from the group consisting of (C4-C 10 In some embodiments, R5 is independently selected from the group consisting of -OR a , -SR a , -N(R a )2, -COR a , -CO2R a , CON(R a )2, -CN, -NC, NO2, N3, -SO2R a , N(R a )COR a , -SO2N(R a )2 and -N(R a )SO2R a In certain embodiments, R5 is independently at each occurrence selected from the group consisting of [ka] In some embodiments, R5 is independently selected from the group consisting of H, D, halogen, OR a , N(R a )2, (C1-C6) alkyl, (C3-C7) heterocycloalkyl, (C1-C6) alkynyl, aryl, (C4-C 10 ) Bicycloalkyl, -CN, -NC, N3, NO2, CORa , CO2R a , CON(R a )2, -SO2R a , N(R a )COR a or -SO2N(R a In certain embodiments, R5 is independently at each occurrence H, D, halogen, (C1-C6)alkyl, (C3-C7)heterocycloalkyl, N(R a )COR a , N(R a )2 or -CN. In certain embodiments, R5, independently at each occurrence, is H, (C1-C6)alkyl, (C1-C6)alkynyl, aryl, (C4-C 10 ) Bicycloalkyl, -SO2R a or -SO2N(R a In certain embodiments, R5 is independently at each occurrence H, D, F, Cl, Br, CH3, CF3, OCH3, NH2, N(CH3)2, [ka] In certain embodiments, R5 is, independently at each occurrence, H, D, F, CH3, N(CH3)2, [ka] is.

[0247] In some embodiments, at least one of R5 is H, D, or halogen. In some embodiments, at least one of R5 is H. In some embodiments, at least one of R5 is D. In some embodiments, at least one of R5 is F. In some embodiments, at least one of R5 is CH3. In some embodiments, at least one of R5 is OCH3. In some embodiments, at least one of R5 is NH2. In some embodiments, at least one of R5 is N(CH3)2. In some embodiments, at least one of R5 is [ka] In some embodiments, at least one of R5 is [ka] In some embodiments, at least one of R5 is [ka] In some embodiments, at least one of R5 is [ka] In some embodiments, at least one of R5 is [ka] In some embodiments, at least one of R5 is [ka] In some embodiments, at least one of R5 is [ka] In some embodiments, at least one of R5 is [ka] , where R a ' is H or (C1-C6) alkyl. In some embodiments, at least one of R5 is [ka] In some embodiments, at least one of R5 is [ka] In some embodiments, at least one of R5 is [ka] In some embodiments, at least one of R5 is [ka] In some embodiments, at least one of R5 is [ka] , where R a ' is H or (C1-C6) alkyl. In some embodiments, at least one of R5 is [ka] In some embodiments, at least one of R5 is [ka] In some embodiments, at least one of R5 is [ka] In some embodiments, at least one of R5 is [ka] In some embodiments, at least one of R5 is [ka] In some embodiments, at least one of R5 is [ka] In some embodiments, at least one of R5 is [ka] In some embodiments, at least one of R5 is -CN. In some embodiments, at least one of R5 is -NC. In some embodiments, at least one of R5 is [ka] In some embodiments, at least one of R5 is [ka] In some embodiments, at least one of R5 is [ka] In some embodiments, at least one of R5 is [ka] In some embodiments, at least one of R5 is NO2. In some embodiments, at least one of R5 is N3. In some embodiments, at least one of R5 is [ka] In some embodiments, at least one of R5 is [ka] is.

[0248] In certain embodiments, R5 is independently at each occurrence halogen, (C1-C6)alkyl, (C1-C6)haloalkyl, OR a , -N(R a )2, -COR a , -CO2R a , CON(R a )2, N(R a )COR a , -CN, NO2, -SO2R a , -SO2N(R a )2, -N(R a )SO2R a , [ka] In some embodiments, at least one of R5 is selected from the group consisting of (C1-C6) alkyl, halogen, OH, NH2, or [ka] In some embodiments, at least one of R5 is CH3, halogen, OH, or NH2. In some embodiments, at least one of R5 is OH. In some embodiments, at least one of R5 is CH3. In some embodiments, at least one of R5 is [ka] is.

[0249] In any of the embodiments described herein, R a is H, (C1-C6) alkyl, (C2-C6) alkenyl, (C3-C7) cycloalkyl, aryl, or heteroaryl. In any of the embodiments described herein, R a At least one of R is aryl or heteroaryl. In any of the embodiments described herein, R a is independently at each occurrence H, (C-C) alkyl, (C-C) alkenyl, or (C-C) cycloalkyl, or two R a are taken together to form a 5- or 6-membered ring optionally substituted with halogen or (C-C) alkyl. In certain embodiments, R a is independently at each occurrence H or (C-C) alkyl. In certain embodiments, R a is independently at each occurrence (C-C)alkenyl. In certain embodiments, R a is independently at each occurrence H, CH, or CHCH. In certain embodiments, R a At least one of R is H or CH. In some embodiments, R a is H in each occurrence. In some embodiments, R a is CH3 in each occurrence. In some embodiments, R aAt least one of R is (C-C)cycloalkyl optionally substituted with halogen or (C-C)alkyl. a at least one of which is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl optionally substituted with halogen or (C1-C6) alkyl.

[0250] In certain embodiments, the structural moiety [ka] teeth [ka] In some embodiments, the structural moiety [ka] teeth [ka] In some embodiments, the structural moiety [ka] teeth [ka] It has the following structure.

[0251] In certain embodiments, the compound of formula Ia [ka] [ka] where R1 is H, (C1-C6) alkyl, N(R a )2, (C3-C7)heterocycloalkyl or halogen; R5 and R 11are each independently H or CH; Y, Y, Y, Y, Z, Z, Z, L, and L are each independently CH or N; and V is NH or O. In some embodiments, the compound of formula Ia is [ka] where R1 is H, (C1-C6) alkyl, N(R a )2, (C3-C7)heterocycloalkyl or halogen; R5 and R 11 are each independently H or CH; Y, Y, Y, Y, Z, Z, Z, L, and L are each independently CH or N; and V is NH or O. In some embodiments, the compound of formula Ia is [ka] where R1 is H, (C1-C6) alkyl, N(R a )2, (C3-C7)heterocycloalkyl or halogen; R5 and R 11 are each independently H or CH; Y, Y, Y, Y, Z, Z, Z, L, and L are each independently CH or N; and V is NH or O. In some embodiments, R is H, F, Cl, Br, CH, CHCH, or CH(CH), [ka] In some embodiments, R1 is [ka] In some embodiments, R1 is [ka] is.

[0252] In certain embodiments, the compound of formula Ib [ka] where R 11 and R5 are each independently H or CH3; and Y1, Y2, Y3, Y4, Z2, Z3 and Z4 are each independently CH or N. In certain embodiments, the compound of formula Ib is [ka] where R 11 and R5 are each independently H or CH3; and Y1, Y2, Y3, Y4, Z2, Z3 and Z4 are each independently CH or N. In certain embodiments, the compound of formula Ib is [ka] where R 11 and R5 are each independently H or CH3; and Y1, Y2, Y3, Y4, Z2, Z3 and Z4 are each independently CH or N.

[0253] In certain embodiments, the compound of Formula Ia, Ib, or Ic activates Akt3, and the compound [ka] In certain embodiments, the compound of Formula Ia, Ib, or Ic activates Akt3 and is Compound 2 shown in Table 2.

[0254] In certain embodiments, the compound of Formula Ia, Ib, or Ic inhibits Akt3, [ka] In certain embodiments, the compound of Formula Ia, Ib, or Ic inhibits Akt3 and is selected from the group consisting of compounds 3 and 18-21 shown in Table 1.

[0255] In certain embodiments, the compound of formula Ia [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] is.

[0256] In certain embodiments, the compound of formula Ia [ka] where R1 is -CONH2, -SO2NH2, -SO2CH3 or [ka] is.

[0257] In certain embodiments, the compound of formula Ia [ka] wherein R1 is -CN or -F and G1 and G2 are -N- and -CH- or -CH- and -N-.

[0258] In certain embodiments, the compound of formula Ia [ka] where R1 is -CONH2, -SO2NH2, -SO2CH3 or [ka] and each of J1, J2, J3, J4, J5, J6 and J7 is independently -N- or -CF.

[0259] In certain embodiments, the compound of formula Ib [ka] [ka] [ka] is.

[0260] In certain embodiments, the compound of formula Ic [ka] is.

[0261] In some embodiments, the compound [ka] is.

[0262] In any of the embodiments disclosed herein, the compound is selected from the group consisting of compounds 2-22 in Examples 2-22, respectively.

[0263] In any of the embodiments disclosed herein, the compound is selected from the group consisting of compounds 3 and 18-21 shown in Table 1.

[0264] In any of the embodiments disclosed herein, the compound is Compound 2 shown in Table 2.

[0265] Prodrug In some embodiments, any of the compounds described herein may be made into a prodrug by attaching a cleavable moiety to one or more functional groups therein. See, for example, J. Med. Chem., Vol. 61, pp. 62-80 (2018); J. Med. Chem., Vol. 61, pp. 6308-6327 (2018); and J. Med. Chem., Vol. 61, pp. 3918-3929 (2018). In some embodiments, the moiety is cleavable upon exposure to a stimulus. Non-limiting examples of such stimuli include temperature, electromagnetic radiation, sonication, pH, solvents, and substances and processes found on or within living organisms. In some embodiments, the cleavable moiety is removed by contact with a living organism. In some embodiments, the cleavable moiety is removed by contact with an enzyme. In some embodiments, the cleavable moiety is removed by contact with alkaline phosphatase. In certain embodiments, the cleavable moiety is a phosphonooxymethyl moiety, which is cleaved as illustrated in Scheme A below. [ka]

[0266] How to Regulate Akt3 Akt3, also known as RAC-gammaserine / threonine-protein kinase, is an enzyme encoded by the Akt3 gene in humans. Akt kinase is a regulator of cell signaling in response to insulin and growth factors, and is known to be involved in a wide range of biological processes, including but not limited to cell proliferation, differentiation, apoptosis, tumorigenesis, glycogen synthesis, and glucose uptake. Akt3 has been shown to be stimulated by platelet-derived growth factor ("PDGF"), insulin, and insulin-like growth factor 1 ("IGF1").

[0267] Akt3 kinase activity mediates the serine and / or threonine phosphorylation of a range of downstream substrates. The nucleic acid sequence of Akt3 is known in the art. See, for example, Genbank accession no. AF124141.1, which is incorporated by reference in its entirety and provides the following nucleic acid sequence: Homo sapiens protein kinase B gamma mRNA, complete cds: AGGGGAGTCATCATGAGCGATGTTACCATTGTGAAGGAAGGTTGGGTTCAGAAGAGGGGA GAATATATAAAAAACTGGAGGCCAAGATACTTCCTTTTGAAGACAGATGGCTCATTCATA GGATATAAAGAGAAACCTCAAGATGTGGATTTACCTTATCCCCTCAACAACTTTTCAGTG GCAAAAATGCCAGTTAATGAAAACAGAACGACCAAAGCCAAACACATTTATAATCAGATGT CTCCAGTGGACTACTGTTATAGAGAGAACATTTCATGTAGATACTCCAGAGGAAAGGGAA GAATGGACAGAAGCTATCCAGGCTGTAGCAGACAGACTGCAGAGGCAAGAAGAGGAGAGA ATGAATTGTAGTCCAACTTCACAAATTGATAATATAGGAGAGGAAGAGATGGATGCCTCT ACAACCCATCATAAAAGAAAGACAATGAATGATTTTGACTATTTGAAACTACTAGGTAAA GGCACTTTTGGGAAAGTTATTTTGGTTCGAGAGAAGGCAAGTGGAAAATACTATGCTATG AAGATTCTGAAGAAAGAAGTCATTATTGCAAAGGATGAAGTGGCACACACTCTAACTGAA AGCAGAGTATTAAAGAACACTAGACATCCCTTTTTAACATCCTTGAAATATTCCTTCCAG ACAAAAGACCGTTTGTGTTTTGTGATGGAATATGTTAATGGGGGCGAGCTGTTTTTCCAT TTGTCGAGAGAGCGGGTGTTCTCTGAGGACCGCACACGTTTCTATGGTGCAGAAATTGTC TCTGCCTTGGACTATCTACATTCCGGAAAGATTGTGTACCGTGATCTCAAGTTGGAGAAT CTAATGCTGGACAAAGATGGCCACATAAAAATTACAGATTTTGGACTTTGCAAAGAAGGG ATCACAGATGCAGCCACCATGAAGACATTCTGTGGCACTCCAGAATATCTGGCACCAGAG GTGTTAGAAGATAATGACTATGGCCGAGCAGTAGACTGGTGGGGCCTAGGGGTTGTCATG TATGAAATGATGTGTGGGAGGTTACCTTTCTACAACCAGGACCATGAGAAACTTTTTGAA TTAATATTAATGGAAGACATTAAATTTCCTCGAACACTCTCTTCAGATGCAAAATCATTG CTTTCAGGGCTCTTGATAAAGGATCCAAATAAACGCCTTGGTGGAGGACCAGATGATGCA AAAGAAATTATGAGACACAGTTTCTTCTCTGGAGTAAACTGGCAAGATGTATATGATAAA AAGCTTGTACCTCCTTTTAAACCTCAAGTAACATCTGAGACAGATACTAGATATTTTGAT GAAGAATTTACAGCTCAGACTATTACAATAACACCACCTGAAAAATATGATGAGGATGGT ATGGACTGCATGGACAATGAGAGGCGGCCGCATTTCCCTCAATTTTCCTACTCTGCAAGT GGACGAGAATAAGTCTCTTTCATTCTGCTACTTCACTGTCATCTTCAATTTATTACTGAA AATGATTCCTGGACATCACCAGTCCTAGCTCTTACACATAGCAGGGGCACCTTCCGACAT CCCAGACCAGCCAAGGGTCCTCACCCCTCGCCACCTTTCACCCTCATGAAAACACACATA CACGCAAATACACTCCAGTTTTTGTTTTTGCATGAAATTGTATCTCAGTCTAAGGTCTCA TGCTGTTGCTGCTACTGTCTTACTATTA (SEQ ID NO: 1).

[0268] The amino acid sequence of Akt3 is also known in the art. See, for example, UniProtKB / Swiss-Prot accession no. Q9Y243 (Akt3_HUMAN), which is incorporated by reference in its entirety and provides the following amino acid sequence: MSDVTIVKEGWVQKRGEYIKNWRPRYFLLKTDGSFIGYKEKPQDVDLPYPLNNFSVAKCQ LMKTERPKPNTFIIRCLQWTTVIERTFHVDTPEEREEWTEAIQAVADRLQRQEEERMNCS PTSQIDNIGEEEMDASTTHHKRKTMNDFDYLKLLGKGTFGKVILVREKASGKYYAMKILK KEVIIAKDEVAHTLTESRVLKNTRHPFLTSLKYSFQTKDRLCFVMEYVNGGELFFHLSRE RVFSEDRTRFYGAEIVSALDYLHSGKIVYRDLKLENLMLDKDGHIKITDFGLCKEGITDA ATMKTFCGTPEYLAPEVLEDNDYGRAVDWWGLGVVMYEMMCGRLPFYNQDHEKLFELILM EDIKFPRTLSSDAKSLLSGLLIKDPNKRLGGGPDDAKEIMRHSFFSGVNWQDVYDKKLVP PFKPQVTSETDTRYFDEEFTAQTITITPPEKYDEDGMDCMDNERRPHFPQFSYSASGRE (SEQ ID NO: 2).

[0269] The domain structure of Akt3 is reviewed in Romano, Scientifica, Volume 2013 (2013), Article ID 317186, page 12, and contains an N-terminal pleckstrin homology domain ("PH") followed by a catalytic kinase domain ("KD") and a C-terminal regulatory hydrophobic region. Both the KD and regulatory domains are important for the biological actions mediated by Akt protein kinases and share the greatest degree of homology among the three Akt isoforms. The PH domain binds lipid substrates such as phosphatidylinositol (3,4) diphosphate ("PIP2") and phosphatidylinositol (3,4,5) triphosphate ("PIP3"). The ATP-binding site is located approximately in the center of the catalytic kinase domain and has a considerable degree of homology with other members of the AGC kinase family, such as p70 S6 kinase ("S6K") and p90 ribosomal S6 kinase ("RSK"), protein kinase A ("PKA"), and protein kinase B ("PKB"). A hydrophobic regulatory moiety is a typical characteristic of the AGC kinase family. SEQ ID NO:2, Akt 3, is generally believed to have the molecular processing and domain structure outlined below. [Table 1]

[0270] The initiating methionine of SEQ ID NO:2 is disposable for Akt3 function. Thus, in certain embodiments, compounds directly or indirectly modulate the expression or bioavailability of Akt3 having the following amino acid sequence: SDVTIVKEGWVQKRGEYIKNWRPRYFLLKTDGSFIGYKEKPQDVDLPYPLNNFSVAKCQ LMKTERPKPNTFIIRCLQWTTVIERTFHVDTPEEREEWTEAIQAVADRLQRQEEERMNCS PTSQIDNIGEEEMDASTTHHKRKTMNDFDYLKLLGKGTFGKVILVREKASGKYYAMKILK KEVIIAKDEVAHTLTESRVLKNTRHPFLTSLKYSFQTKDRLCFVMEYVNGGELFFHLSRE RVFSEDRTRFYGAEIVSALDYLHSGKIVYRDLKLENLMLDKDGHIKITDFGLCKEGITDA ATMKTFCGTPEYLAPEVLEDNDYGRAVDWWGLGVVMYEMMCGRLPFYNQDHEKLFELILM EDIKFPRTLSSDAKSLLSGLLIKDPNKRLGGGPDDAKEIMRHSFFSGVNWQDVYDKKLVP PFKPQVTSETDTRYFDEEFTAQTITITPPEKYDEDGMDCMDNERRPHFPQFSYSASGRE (SEQ ID NO: 3).

[0271] Two specific sites, one in the kinase domain (Thr-305 with reference to SEQ ID NO:2) and the other in the C-terminal regulatory region (Ser-472 with reference to SEQ ID NO:2), must be phosphorylated for full activation of Akt3. Interaction between the PH domain of Akt3 and TCL1A enhances Akt3 phosphorylation and activation. IGF-1 leads to activation of Akt3, which may have a role in regulating cell survival.

[0272] In certain embodiments, compounds of Formula Ia, Ib, or Ic described herein are inhibitors of Akt3. In other embodiments, compounds of Formula Ia, Ib, or Ic described herein are activators of Akt3.

[0273] Pharmaceutical Composition Some aspects of the invention involve administering to a subject an effective amount of a composition to achieve a particular outcome. Small molecule compositions useful according to the methods of the invention may therefore be formulated in any manner suitable for pharmaceutical use.

[0274] The formulations of the present invention are administered in pharmaceutically acceptable solutions which may contain concentrations of salts, buffers, preservatives, compatible carriers, adjuvants and optionally other therapeutic ingredients conventionally accepted in the pharmaceutical arts.

[0275] For use in therapy, an effective amount of the compound can be administered to a subject by any method that allows the compound to be taken up by the appropriate target cells. "Administration" of the pharmaceutical composition of the present invention can be achieved by any means known to those skilled in the art. Specific administration routes include, but are not limited to, oral, transdermal (e.g., via a patch), parenteral injection (subcutaneous, intradermal, intramuscular, intravenous, intraperitoneal, intrathecal, etc.), or mucosal (intranasal, intratracheal, inhalation, rectal, intravaginal, etc.). Injection can be by bolus or continuous infusion.

[0276] For example, the pharmaceutical compositions of the present invention can be administered intravenously, intramuscularly, or by other parenteral means. They can also be administered intranasally, by inhalation, topically, orally, or by implant; rectal or vaginal use is also possible. Suitable liquid or solid pharmaceutical formulations can be, for example, aqueous or saline solutions for injection or inhalation, microencapsulated, cochleated, coated on microscopic gold particles, liposome-encapsulated, sprayed, aerosolized, pellets for skin implantation, or dried on a sharp object for skin imprinting. Pharmaceutical compositions also include granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, drops, or formulations for extended release of active compounds, in which additives and / or auxiliaries such as disintegrants, binders, coating agents, swelling agents, lubricants, flavoring agents, sweeteners, or solubilizers are conventionally used, as described above. The pharmaceutical compositions are suitable for use in a variety of drug delivery systems. For a brief review of this method for drug delivery, see Langer R (1990) Science 249:1527-33.

[0277] The concentration of the compound contained in the composition used in the method of the present invention can range from about 1 nM to about 100 μM. Effective doses are expected to range from about 10 picomoles / kg to about 100 micromoles / kg.

[0278] Pharmaceutical compositions are preferably prepared and administered in dosage units. Liquid dosage units are vials or ampoules for injection or other parenteral administration. Solid dosage units are tablets, capsules, powders, and suppositories. For the treatment of patients, different dosages may be required depending on the activity of the compound, the method of administration, the purpose of administration (i.e., prevention or treatment), the nature and severity of the disorder, and the age and weight of the patient. The administration of a certain dose can be carried out by both a single administration in the form of individual dosage units or several small dosage units. Multiple repetitions and multiple administrations at specific intervals separated by days, weeks, or months are also contemplated by the present invention.

[0279] The composition may be administered per se (undiluted) or in the form of a pharmaceutically acceptable salt. When used in medicine, the salt must be pharmaceutically acceptable, but non-pharmaceutically acceptable salts may be conveniently used to prepare pharmaceutically acceptable salts. Such salts include, but are not limited to, those prepared from the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, maleic acid, acetic acid, salicylic acid, TsOH (p-toluenesulfonic acid), tartaric acid, citric acid, methanesulfonic acid, formic acid, malonic acid, succinic acid, naphthalene-2-sulfonic acid, and benzenesulfonic acid. These salts may also be prepared as alkali metal or alkaline earth salts, such as sodium, potassium, or calcium salts of the carboxylic acid group.

[0280] Suitable buffering agents include acetic acid and salts (1-2% w / v), citric acid and salts (1-3% w / v), boric acid and salts (0.5-2.5% w / v), and phosphoric acid and salts (0.8-2% w / v). Suitable preservatives include benzalkonium chloride (0.003-0.03% w / v), chlorobutanol (0.3-0.9% w / v), parabens (0.01-0.25% w / v), and thimerosal (0.004-0.02% w / v).

[0281] Compositions suitable for parenteral administration conveniently include sterile aqueous preparations that can be isotonic with the recipient's blood. Among the acceptable vehicles and solvents are water, Ringer's solution, phosphate-buffered saline, and isotonic sodium chloride solution. Furthermore, sterile, fixed oils are conveniently used as solvents or suspending media. For this purpose, any non-irritating fixed mineral oil or non-mineral oil, including synthetic mono- or diglycerides, can be used. Furthermore, fatty acids such as oleic acid are useful for injectable preparations. Carrier formulations suitable for subcutaneous, intramuscular, intraperitoneal, intravenous, and other administrations can be found in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA.

[0282] The compounds useful in the present invention may be delivered in a mixture of more than two such compounds, which mixture may further include one or more adjuvants in addition to the combination of compounds.

[0283] A variety of administration routes are available. The particular method selected will naturally depend on the particular compound selected, the age and general health of the subject, the particular condition being treated, and the dosage required for therapeutic effectiveness. The method of the present invention can be carried out using any medically acceptable administration method, meaning any method that produces an effective level of response without causing clinically unacceptable adverse effects. Preferred administration methods are described above.

[0284] The composition can be conveniently presented in unit dosage form, and can be prepared by any method known in the pharmaceutical field.All methods include the step of mixing the compound with the carrier that constitutes one or more auxiliary components.Generally, the composition is prepared by uniformly and intimately mixing the compound with liquid carrier, finely divided solid carrier or both, and then, if necessary, shaping the product.

[0285] Other delivery systems may include sequential sustained-release, delayed-release, or sustained-release delivery systems. Such systems avoid repeated administration of the compound and are more convenient for patients and physicians. Many types of delivery systems are available and known to those skilled in the art. These include polymer-based systems such as poly(lactide-glycolide), copolyoxalic acid, polycaprolactonic acid, polyesteramides, polyorthoesters, polyhydroxybutyric acid, and polyanhydrides. Microcapsules of these polymers containing drugs are described, for example, in U.S. Patent 5,075,109. Delivery systems also include non-polymeric systems, including lipids, including sterols such as cholesterol, cholesterol esters, and fatty acids or neutral lipids such as mono-, di-, and triglycerides; hydrogel release systems; silastic systems; peptide-based systems; wax coatings; compressed tablets using conventional binders and additives; and partially condensed implants. Specific examples include, but are not limited to, (a) erosion systems in which the agents of the invention are contained within a matrix, such as those described in U.S. Patents 4,452,775, 4,675,189, and 5,736,152, and (b) diffusion systems in which the active ingredient permeates through a polymer at a controlled rate, such as those described in U.S. Patents 3,854,480, 5,133,974, and 5,407,686. Additionally, pump-based hardware delivery systems can be used, some of which are suitable for implantation.

[0286] Disease Treatment Methods In other embodiments, a method of treating a disease in a subject in need thereof comprises administering to the subject an effective amount of a compound of Formula Ia, Ib, or Ic described herein.

[0287] In some embodiments, the disease is selected from the group consisting of neurodegenerative diseases, cachexia, eating disorders, obesity, complications of obesity, inflammatory diseases, virally induced inflammatory responses, Gulf War syndrome, tuberous sclerosis, retinitis pigmentosa, transplant rejection, cancer, autoimmune diseases, ischemic tissue injury, traumatic tissue injury, and combinations thereof.

[0288] In some embodiments, compounds of Formula Ia, Ib, or Ic regulate Akt3 in immune cells. Non-limiting examples of immune cells include T cells (e.g., T regulatory cells ("Treg")), B cells, macrophages, and glial cells (e.g., astrocytes, microglia, or oligodendrocytes). In some embodiments, the immune cells are Tregs. In some embodiments, compounds of Formula Ia, Ib, or Ic activate Akt3 signaling. In other embodiments, compounds of Formula Ia, Ib, or Ic inhibit Akt3 signaling. In some embodiments, compounds of Formula Ia, Ib, or Ic regulate Akt3 in Tregs. The present inventors have surprisingly discovered that in some embodiments, compounds of Formula Ia, Ib, or Ic increase Treg activity or production, while in other embodiments, the compounds decrease Treg activity or production. The inventors have also surprisingly discovered that in certain embodiments, compounds of Formula Ia, Ib, or Ic activate Akt3 signaling, while in other embodiments, the compounds inhibit Akt3 signaling.

[0289] Neurodegenerative diseases In some embodiments, a method for treating or preventing neurodegenerative diseases in a subject in need thereof is described, comprising regulating Akt3 signaling by administering to the subject an effective amount of a compound of Formula Ia, Ib or Ic as described herein.In some embodiments, the neurodegenerative disease is selected from the group consisting of Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, motor neuron disease, Huntington's disease, HIV-induced neurodegeneration, Lewy body disease, spinal muscular atrophy, prion disease, spinocerebellar ataxia, familial amyloidotic polyneuropathy, multiple sclerosis, and combinations thereof.

[0290] Neurodegenerative diseases occur when nerve cells in the brain or peripheral nervous system lose function over time and eventually die. In many neurodegenerative diseases, chronic neuroinflammation contributes to disease progression. Current treatments help alleviate some of the physical or mental symptoms associated with neurodegenerative diseases, but there is currently no way to slow disease progression, and there is no known cure.

[0291] Although the mechanisms that trigger neurodegenerative processes are unknown, increasing evidence suggests a critical role for immunity and the immune system in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, spinal muscular atrophy, familial amyloidotic polyneuropathy, and ALS. Tregs, CD4 T cells, suppress immune responses and are essential mediators of self-tolerance and immune homeostasis. + Tregs are a subset of T cells (see Sakaguchi, et al., Cell, 133, 775-787 (2008)). Evidence suggests that Tregs play an important role in the progression of neurodegenerative diseases. For example, Akt3 can regulate the suppressive function of natural Tregs and the polarization of inducible Tregs; therefore, Akt3 modulation in immune cells can regulate immune responses. More specifically, Akt3 in activated immune cells can induce immunosuppressive responses, while Akt3 inhibition in immune cells can induce immunosuppressive response phenomena. Without being bound by any one theory, it is believed that modulation of Akt3 signaling in immune cells can be used to treat and prevent neurodegenerative diseases.

[0292] In some embodiments, a method for treating or preventing a neurodegenerative disease in a subject in need thereof is described, comprising administering to the subject an Akt3 activator, such as a compound of Formula Ia, Ib, or Ic, described herein, in an effective amount to induce an immunosuppressive response and treat or delay the progression of the disease. In some embodiments, the Akt3 activator regulates the immune response by increasing the inhibitory function of immunosuppressive cells. In some embodiments, Akt3 is selectively activated in immune cells. Examples of immune cells include, but are not limited to, T cells, B cells, macrophages, and glial cells such as astrocytes, microglia, and oligodendrocytes. In a preferred embodiment, Akt3 is activated in Tregs. In some embodiments, the Akt3 activator can also be used to increase or promote the activity or production of Tregs, increase the production of cytokines such as IL-10 from Tregs, increase the differentiation of Tregs, increase the number of Tregs, or increase the survival of Tregs.

[0293] In one embodiment, a method for treating or preventing neurodegenerative diseases in a subject in need thereof is described, comprising administering to the subject an Akt3 inhibitor of a compound of Formula Ia, Ib, or Ic described herein in an effective amount to inhibit immunosuppressive responses and treat or prevent the progression of the disease. In one embodiment, the Akt3 inhibitor of a compound of Formula Ia, Ib, or Ic described herein regulates immune responses by reducing immunosuppressive responses or increasing immunostimulatory responses. In one embodiment, Akt3 is selectively inhibited in immune cells. Examples of immune cells include, but are not limited to, T cells, B cells, macrophages, and glial cells such as astrocytes, microglia, and oligodendrocytes. In a preferred embodiment, Akt3 is inhibited in Tregs.

[0294] In some embodiments, a compound of Formula Ia, Ib, or Ic can treat or prevent ALS. ALS, also known as Lou Gehrig's disease, is a progressive neurodegenerative disease that affects motor neurons in the brain and spinal cord. Symptoms of ALS include, but are not limited to, difficulty speaking, swallowing, walking, moving, and breathing. ALS typically affects men and women between the ages of 40 and 70. There are two distinct types of ALS: sporadic and familial. Sporadic ALS, the most common form of the disease in the United States, accounts for 90 to 95 percent of all cases. Familial ALS is associated with mutations in Cu / Zn superoxide dismutase (SOD1). Oxidative stress, mitochondrial dysfunction, excitotoxicity, protein aggregation, endoplasmic reticulum stress, axonal transport dysfunction, dysregulated neuron-glia interactions, and apoptosis have all been shown to contribute to motor neuron injury in the presence of mutant OD1. Without being bound by any one theory, it is believed that Treg dysfunction plays a role in the progression of ALS, and that administration of an Akt3 modulator may treat or prevent the progression of ALS. Some subjects with rapidly progressing ALS have a deficiency in the Treg master transcription factor FOXP3, which leads to dysfunction of Treg suppressive function. One embodiment provides a method for treating ALS in a subject in need thereof, comprising administering to the subject in need thereof an Akt3 activator in an amount effective to activate Akt3 in immune cells and induce an immunosuppressive response. In a preferred embodiment, Akt3 is activated in Tregs.

[0295] In certain embodiments, administration of an Akt3 activator of Formula Ia, Ib, or Ic described herein to a subject with ALS slows disease progression and prolongs the subject's survival.

[0296] For example, other motor neuron diseases may be treated or prevented using the disclosed Akt3 modulators, including progressive bulbar palsy, pseudobulbar palsy, primary lateral sclerosis, spinal muscular atrophy, and post-polio syndrome.

[0297] Parkinson's disease is a neurodegenerative disorder that primarily affects dopamine-producing neurons in a specific area of ​​the brain called the substantia nigra. Parkinson's disease is a progressive disease that worsens over time as more neurons become damaged or die. The cause of neuronal cell death in Parkinson's is unknown. Symptoms of Parkinson's disease include, but are not limited to, tremors in the hands, arms, legs, jaw, or head, stiffness of the limbs and trunk, slowness of movement, and impaired balance and coordination.

[0298]

[0009] Certain embodiments provide methods for treating Parkinson's disease, comprising administering to a subject in need thereof an Akt3 modulator in an amount effective to activate or inhibit Akt3 in immune cells and induce an immunosuppressive response. In certain embodiments, administration of an Akt3 activator to a subject with Parkinson's disease slows or stops disease progression to unaffected areas of the brain.

[0299] In some embodiments, the Akt3 activators of Formula Ia, Ib, or Ic disclosed herein can be administered prophylactically to a subject if the subject has a family history of Parkinson's disease or other neurodegenerative diseases. In some embodiments, the Akt3 activators protect neurons from disease induction or slow the onset of disease.

[0300] Huntington's disease is a progressive neurodegenerative disease.This disease is characterized by the progressive destruction of nerve cells in the brain.Symptoms of Huntington's disease include but are not limited to involuntary movement problems and dysfunction in voluntary movement, such as involuntary spasms, muscle rigidity, slow or abnormal eye movements, impaired gait, posture and balance, difficulty in physical output of speech or swallowing; cognitive dysfunction, such as difficulty in organizing, prioritizing or consolidating tasks, inflexibility or tendency to fixate on one thought, action or activity, lack of impulse control, lack of awareness of one's own actions and abilities, slowness of thought or word-finding and difficulty in learning new information; and psychiatric disorders, such as depression.In some embodiments, the Akt3 modulator disclosed can alleviate the symptoms or delay the progression of Huntington's disease.

[0301] One embodiment provides a method for treating Huntington's disease in a subject in need thereof by administering an Akt3 modulator to the subject in an amount effective to activate or inhibit Akt3 in immune cells and induce an immunosuppressive response. In one embodiment, the Akt3 modulator slows or stops the progression of disease symptoms in a subject with Huntington's disease. In another embodiment, the Akt3 modulator can alter the Treg / Th17 balance.

[0302] Huntington's disease is largely hereditary; all children of parents with Huntington's disease have a 50 / 50 chance of inheriting the disease. In certain embodiments, subjects with a family history of Huntington's disease can be prophylactically administered the disclosed Akt3 modulators before disease symptoms appear, preventing or slowing the onset of disease symptoms.

[0303] Alzheimer's disease is a progressive disorder that causes brain cell degeneration and eventual death. Alzheimer's disease is the most common cause of dementia and is characterized by a gradual decline in thinking, behavioral, and social skills that interferes with a person's ability to function independently. Symptoms of Alzheimer's disease include, but are not limited to, memory loss, impaired thinking and reasoning abilities, difficulty making judgments and decisions, and personality and behavioral changes. While the exact cause of Alzheimer's disease is not fully understood, the core problem is thought to be dysfunction in brain proteins that disrupt neuronal function and unleash a cascade of toxic events. Damage most frequently begins in areas of the brain that control memory, but this process begins several years before the first symptoms. Neuronal loss spreads to other areas of the brain in a somewhat predictable pattern. In the later stages of the disease, the brain significantly shrinks. Beta-amyloid plaques and tau protein tangles most frequently contribute to the majority of neuronal damage and dysfunction in Alzheimer's disease.

[0304] One embodiment provides a method of treating Alzheimer's disease in a subject by administering to the subject an Akt3 activator in an amount effective to hyperactivate Akt3 in Tregs and activate downstream neuroprotective pathways in the brain. In another embodiment, the subject is administered an effective amount of an Akt3 activator that reduces or eliminates symptoms of Alzheimer's disease or slows disease progression.

[0305] Another embodiment provides a method of treating or preventing the progression of Alzheimer's disease in a subject by administering to the subject an Akt3 inhibitor of Formula Ia, Ib, or Ic described herein in an amount effective to inhibit Akt3 in Tregs and induce an immune response or reduce an immunosuppressive response. In certain embodiments, inhibition of Akt3 in Tregs leads to beta-amyloid plaque clearance, attenuation of the neuroinflammatory response, and recovery from cognitive decline.

[0306] Spinal muscular atrophy ("SMA") is a group of chronic neuromuscular diseases characterized by progressive loss of motor neurons and muscle wasting. SMA is commonly classified into four types that differ in severity and the life stage during which the disease manifests. These types are: SMA1 or Werdnig-Hoffmann disease ("pediatric" SMA), which manifests between 0 and 6 months of age; SMA2 or Dubowitz disease, which manifests between 6 and 18 months of age ("intermediate" SMA); SMA3 or Kugelberg-Welander disease, which manifests after age 1 year ("juvenile" SMA); and SMA4, which develops during adulthood ("adult-onset" SMA). The most severe form, SMA1, is sometimes referred to as SMA0 ("severe pediatric" SMA). Signs and symptoms of SMA vary by type, but the most common include, but are not limited to, a lack of stability or tendency to fall, difficulty sitting, standing, or walking, loss of respiratory muscle strength, spasms, and difficulty eating and swallowing. All types of SMA are associated with exon deletions and / or point mutations in the SMN1 gene that block expression of the SMN protein. Depending on the type, SMA can be treated with various gene therapies, nutritional and respiratory support, orthopedic surgery, or combinations thereof. Neuroprotective drugs hold promise as a way to stabilize motor neuron loss, but currently available candidates have not yet fully advanced successfully in clinical trials. Therefore, additional candidate neuroprotective drugs are needed for the treatment of SMA.

[0307]

[0013] Certain embodiments provide methods of treating SMA in a subject by administering to the subject an Akt3 modulator of Formula Ia, Ib, or Ic described herein in an amount effective to allow motor neuron survival. In other embodiments, the subject is administered an effective amount of an Akt3 modulator that reduces or eliminates symptoms of SMA or slows disease progression.

[0308] Multiple sclerosis ("MS") is a disease in which nerve cells in the brain and spinal cord demyelinate, leading to neuronal damage and disruption of signal transduction throughout the nervous system. People with MS can experience almost any neurological sign / symptom, with autonomic, visual, motor, and sensory dysfunction being the most common. The exact cause of MS is unknown, but it is thought to be a combination of genetic factors, such as chromosomal abnormalities in the major histocompatibility complex, and environmental factors, such as exposure to infectious and toxin-related agents. Treatments for MS, including but not limited to medications and physical therapy, attempt to restore function in affected areas after an acute attack and prevent the occurrence of new attacks. There is no known cure for MS, and many current medications, while moderately effective, have severe side effects and can be poorly tolerated. Therefore, new medications are needed for safe, effective, reversible, and preventative treatment of MS.

[0309]

[0013] Certain embodiments provide methods of treating MS in a subject by administering to the subject an Akt3 modulator of Formula Ia, Ib, or Ic described herein in an amount effective to restore post-ictal loss of function and / or prevent a seizure from occurring. In other embodiments, the subject is administered an effective amount of an Akt3 activator that reduces or eliminates symptoms of MS or slows disease progression.

[0310] weight loss In some embodiments, disclosed herein are methods for treating or preventing extreme weight loss, comprising administering a compound disclosed herein to a subject in need thereof. Non-limiting examples of weight loss disorders include cachexia, eating disorders, and anorexia nervosa. An exemplary method comprises inhibiting Akt3 in a subject in need thereof by administering a compound of Formula Ia, Ib, or Ic described herein. Without being bound by any one theory, Akt3 is believed to play an important role in adipogenesis. White adipogenesis requires the activation of a transcriptional cascade involving the sequential induction of several transcription factors, including, but not limited to, FOXO1, several members of the C / EBP family, and PPARγ. FOXO1 is an essential negative regulator of adipogenesis and is primarily regulated by phosphorylation / acetylation of multiple residues by enzymes including Akt. FOXO1 can also be regulated by the serine / threonine protein kinase SGK1. SGK1 is downstream of PI3K and can inhibit FOXO1 by phosphorylation. SGK1 is regulated by the serine / threonine protein kinase WNK1, which can also be regulated by Akt and SGK1. Akt3 suppresses adipogenesis through the phosphorylation of WNK1, leading to the downregulation of SGK1 activity and SGK1-mediated inhibition of FOXO1. In some embodiments, inhibition of Akt3 in Tregs can promote adipogenesis and reverse disease-induced weight loss.

[0311] Cachexia, or wasting syndrome, is a multifactorial syndrome characterized by progressive skeletal muscle loss that cannot be fully reversed with conventional nutritional support, leading to progressive functional impairment. Cachexia is so devastating that the body utilizes other energy sources, namely skeletal muscle and adipose tissue, when it senses nutritional insufficiency. It affects the majority of advanced cancer patients and is associated with poor infection-fighting ability, treatment tolerance, response to therapy, quality of life, and life expectancy. In certain embodiments, cachexia is caused by chronic diseases, including, but not limited to, cancer, inflammatory diseases, neurodegenerative diseases, pathogenic infections, immunodeficiency disorders, weight gain disorders, weight loss disorders, hormonal imbalances, tuberous sclerosis, retinitis pigmentosa, congestive heart failure, and combinations thereof. Certain embodiments provide methods for treating cachexia in a subject in need thereof by administering to the subject an Akt3 inhibitor, a compound of Formula Ia, Ib, or Ic, described herein, in an amount effective to reduce the symptoms of cachexia. Another embodiment provides a method for promoting weight gain in a subject in need thereof by administering to the subject an Akt3 inhibitor, such as a compound of Formula Ia, Ib, or Ic described herein, in an amount effective to promote adipogenesis in the subject. In some embodiments, an Akt3 inhibitor may be administered prophylactically to a subject suspected of being susceptible to cachexia (e.g., a subject diagnosed with cancer or other disease) to prevent or slow the onset of cachexia syndrome. In some embodiments, the compounds disclosed herein are used to treat cachexia by modulating Akt3, rather than by modulating T regulatory cells.

[0312] Anorexia nervosa is an eating disorder characterized by weight loss or lack of weight gain in growing children, difficulty maintaining a weight appropriate for height, age, and stature, and often a distorted body image. One of the primary goals of treating eating disorders is to restore normal body weight. In some embodiments, the compounds disclosed herein of Formula Ia, Ib, or Ic inhibit Akt3, which is overactivated by increased estradiol levels in subjects with eating disorders. In some embodiments, the compounds disclosed herein of Formula Ia, Ib, or Ic can be used to treat eating disorders. In some embodiments, the disclosed Akt3 inhibitor compounds of Formula Ia, Ib, or Ic are administered to subjects diagnosed with an eating disorder in an effective amount to promote adipogenesis and reverse extreme weight loss.

[0313] Obesity and its complications Conditions characterized by weight gain (e.g., obesity) affect 40% of adults and 20% of children and adolescents in the United States alone, and the numbers are on the rise. See “Overweight & Obesity: Data & Statistics,” US Centers for Disease Control and Prevention, accessed April 3, 2020. >30 kg / m 2 Obesity, characterized by a body mass index of 0.01 or higher, increases the risk of various diseases (e.g., cardiovascular disease and type 2 diabetes). Akt3 activation has been shown to protect against obesity. In some embodiments, a method for treating obesity comprises administering an Akt3 activator to a subject who is obese or at risk of becoming obese in an amount effective to reverse or prevent the effects of the disease.

[0314] In some embodiments, the compounds disclosed herein that modulate Akt3 are used to treat obesity and / or complications of obesity. In some embodiments, the complications of obesity are selected from the group consisting of glucose intolerance, fatty liver, dyslipidemia, and combinations thereof. In some embodiments, the compounds disclosed herein are used to treat obesity and / or complications of obesity by modulating Akt3, but not by modulating T regulatory cells.

[0315] inflammatory diseases Akt3 signaling is associated with chronic or acute inflammation, which contributes to inflammatory diseases. One embodiment provides a method for treating or preventing inflammatory diseases in a subject in need thereof, comprising administering to the subject a composition comprising an Akt3 modulator in an amount effective to regulate Akt3 signaling and treat or delay the progression of the disease. In one embodiment, the Akt3 modulator activates Akt3 signaling and / or increases Treg activity or production, resulting in an immunosuppressive effect.

[0316] Non-limiting examples of inflammatory diseases include atopic dermatitis, allergies, asthma, and combinations thereof.

[0317] Virus-induced inflammatory response Akt3 signaling is associated with acute immune responses resulting from virus-induced inflammatory diseases, such as severe acute respiratory syndrome ("SARS") and coronavirus disease 2019 ("COVID-19"). Thus, in certain embodiments, a method of treating a virus-induced inflammatory disease in a subject in need thereof comprises administering to the subject an Akt3 modulator in an amount effective to reverse or slow disease progression.

[0318] cancer In some embodiments, a method for treating or preventing cancer in a subject in need thereof is provided, comprising regulating Akt3 signaling by administering to the subject an effective amount of a compound of Formula Ia, Ib, or Ic described herein. In some embodiments, the compound of Formula Ia, Ib, or Ic inhibits Akt3 signaling and / or reduces Treg activity or production, resulting in an immune response activation effect.

[0319] In some embodiments, the cancer is selected from the group consisting of bladder cancer, brain cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, kidney cancer, liver cancer, lung cancer, nasopharyngeal cancer, pancreatic cancer, prostate cancer, skin cancer, gastric cancer, uterine cancer, ovarian cancer, testicular cancer, adult T-cell leukemia / lymphoma, and combinations thereof.

[0320] In some embodiments, the compounds and compositions disclosed herein are useful for treating leukemia. In some embodiments, the compounds and compositions disclosed herein that inhibit Akt3 are useful for treating leukemia. In these embodiments, the compounds and compositions disclosed herein that inhibit Akt3 are useful in vivo and ex vivo as immune response stimulating therapies. The ability to inhibit Akt3 and therefore inhibit or reduce Treg-mediated immunosuppression allows for a more robust immune response. In some embodiments, the compounds and compositions disclosed herein are also useful for stimulating or enhancing immune stimulatory or activation responses involving T cells. In some embodiments, the compounds and compositions disclosed herein are useful for stimulating or enhancing an immune response in a host for the treatment of leukemia by selectively inhibiting Akt3. In these embodiments, the compounds and compositions disclosed herein can be administered to a subject in an amount effective to stimulate T cells in the subject. Types of leukemia that can be treated with the compounds and compositions disclosed herein include, but are not limited to, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), adult T-cell leukemia / lymphoma (ATLL), and chronic myelomonocytic leukemia (CMML).

[0321] In some embodiments, ATLL is almost exclusively diagnosed in adults, with a median age in the mid-60s. In some embodiments, there are four types of ATLL: (1) acute, (2) chronic, (3) smoldering, and (4) lymphomatous. In some embodiments, acute ATLL is the most common form and is characterized by high white blood cell counts, hypercalcemia, organomegaly, and elevated lactose dehydrogenase levels. In some embodiments, lymphomatous ATLL manifests in lymph nodes and accounts for less than 1% of circulating lymphocytes. In some embodiments, chronic and smoldering ATLL are characterized by a less aggressive clinical course and the potential for long-term survival. In some embodiments, the four-year survival rates for acute and lymphomatous ATLL are less than 5%. In some embodiments, the four-year survival rates for chronic and smoldering forms of ATLL are 26.9% and 62%, respectively. In some embodiments, adult T-cell leukemia / lymphoma is caused by human T-cell lymphotropic virus 1 (HTLV-1).

[0322] In some embodiments, the compounds and compositions disclosed herein are useful for treating ATLL. In some embodiments, the compounds and compositions disclosed herein that inhibit Akt3 are useful for treating ATLL. In some embodiments, Tregs that express CD25 and FoxP3 transform into ATLL cells. In some embodiments, ATLL cells exhibit an activated helper / inducer T cell phenotype but exhibit strong immunosuppressive activity. In some embodiments, the compounds and compositions disclosed herein that inhibit Akt3 reduce the immunosuppressive response of ATLL cells. In other embodiments, the compounds and compositions disclosed herein that inhibit Akt3 enhance the immunostimulatory response and overcome the strong immunosuppressive activity of ATLL cells.

[0323] In certain embodiments, the compounds and compositions disclosed herein that are useful for treating leukemia or ATLL reduce or inhibit immunosuppressive responses, including, but not limited to, the immunosuppressive function of natural Treg (nTreg) cells and the induction of conventional T cells into inducible Treg (iTreg). In these embodiments, the immunosuppressive function in nTreg cells that is reduced or inhibited is the secretion of one or more anti-inflammatory cytokines, such as, but not limited to, IL10, TGFβ, or a combination thereof. In certain embodiments, a method for treating leukemia or adult T-cell leukemia / lymphoma includes administering to a subject a second active agent, such as, but not limited to, an anti-nausea drug, a chemotherapy drug, or a potentiating agent (e.g., cyclophosphamide).

[0324] autoimmune diseases In some embodiments, the disease is an autoimmune disease. Non-limiting examples of autoimmune diseases include achalasia, Addison's disease, adult Still's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-glomerular basement membrane disease, anti-tubular basement membrane nephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmune dysautonomia, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease, autoimmune myocarditis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune urticaria, axonal and neuronal neuropathy, Baro's disease, Behcet's disease, benign mucous membrane pemphigoid, and rheumatoid arthritis. Pemphigus, Castleman's disease, celiac disease, Chagas' disease, chronic inflammatory demyelinating polyneuropathy, chronic relapsing multifocal osteomyelitis, Churg-Strauss syndrome, eosinophilic granulomatosis, cicatricial pemphigoid, Cogan's syndrome, cold agglutinin disease, congenital heart block, Coxsackie-myocarditis, CREST syndrome, Crohn's disease, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus, Dressler's syndrome, endometriosis, eosinophilic esophagitis, eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, Evans' syndrome, fibromyalgia, fibrosis Alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture's syndrome, granulomatosis with polyangiitis, Graves' disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schönlein purpura, pemphigoid of pregnancy, hidradenitis suppurativa (acne inversa), hypogammaglobulinemia, IgA nephropathy, IgG4-related sclerosing disease, immune thrombocytopenic purpura, inclusion body myositis, interstitial cystitis, juvenile arthritis, juvenile diabetes mellitus (type 1 diabetes), juvenile myositis, Kawasaki disease, Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosus, xylophilic erythrombocytopenic purpura conjunctivitis, linear IgA disease, lupus, chronic Lyme disease, Meniere's disease, microscopic polyangiitis, mixed connective tissue disease, Mooren's ulcer, Mukka-Habermann disease, multifocal motor neuropathy, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neonatal lupus, neuromyelitis optica, neutropenia, ocular cicatricial pemphigoid, optic neuritis, relapsing rheumatism, pediatric autoimmune neuropsychiatric disorders, paraneoplastic cerebellar degeneration, paroxysmal nocturnal hemoglobinuria, Parry-Romberg syndrome, pars planitis (peripheral uveitis), Parsonage-Turner syndrome, pemphigus, peripheral neuropathy,Perivenous encephalomyelitis, pernicious anemia, POEMS syndrome, polyarteritis nodosa, polyglandular syndrome type I, polyglandular syndrome type II, polyglandular syndrome type III, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, post-pericardiotomy syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, progestational dermatitis, psoriasis, psoriatic arthritis, pure red cell aplasia, pyoderma gangrenosum, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, relapsing polychondritis, restless legs syndrome group, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt's syndrome, scleritis, scleroderma, Sjögren's syndrome, sperm and testicular autoimmunity, stiff-body syndrome, subacute bacterial endocarditis, Susac's syndrome, sympathetic ophthalmia, Takayasu's arteritis, temporal arteritis (giant cell arteritis), thrombocytopenic purpura, Tolosa-Hunt syndrome, transverse myelitis, ulcerative colitis, undifferentiated connective tissue disease, uveitis, vasculitis, leukoplakia, and Vogt-Koyanagi-Harada disease.

[0325] Other indications In some embodiments, the compounds disclosed herein regulate Akt3 and are used to treat Gulf War syndrome, tuberous sclerosis, retinitis pigmentosa, transplant rejection, ischemic tissue injury, or traumatic tissue injury. In some embodiments, the transplant rejection is graft-versus-host disease. In some embodiments, the compounds disclosed herein are used to treat retinitis pigmentosa by regulating Akt3, rather than by regulating T regulatory cells. In some embodiments, the compounds disclosed herein are used to treat ischemic tissue injury or traumatic tissue injury. In some embodiments, the ischemic tissue injury or traumatic tissue injury is cerebral ischemic tissue injury or traumatic tissue injury.

[0326] Combination treatment methods In some embodiments, the disclosed compound can be administered to a subject in need thereof alone or in combination with one or more additional therapeutic agents.In some embodiments, the compound and the additional therapeutic agent are administered separately but simultaneously.In some embodiments, the compound and the additional therapeutic agent are administered as part of the same composition.In other embodiments, the compound and the second therapeutic agent are administered separately at different times but as part of the same treatment regimen.

[0327] In some embodiments, the subject may receive the first therapeutic agent 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours or more, or 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days or more, before the administration of the second therapeutic agent. In some embodiments, the subject may receive the first agent one or more times every 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 14 days, 21 days, 28 days, 35 days, or 48 days before the single administration of the second agent. The compounds disclosed herein can be first or second therapeutic agents.

[0328] In some embodiments, compound and additional therapeutic agent can be administered as part of treatment regimen.For example, if the first therapeutic agent can be administered to the subject every 4 days, the second therapeutic agent can be administered on the first, second, third or fourth day or combination thereof.The first therapeutic agent or the second therapeutic agent can be repeatedly administered throughout the entire treatment regimen.

[0329] Examples of additional therapeutic agents include, but are not limited to, cytokines, chemotherapeutic agents, radioisotopes, other immunotherapies, enzymes, antibiotics, antivirals (e.g., protease inhibitors alone or in combination with nucleosides for HIV or Hepatitis B or C), antiparasitics (e.g., helminths or protozoans), growth factors, growth inhibitory agents, hormones, hormone antagonists, antibodies and biologically active fragments thereof (including humanized, single chain and chimeric antibodies), antigen and vaccine formulations (including adjuvants), peptide drugs, anti-inflammatory agents, ligands that bind toll-like receptors to activate the innate immune system (including, but not limited to, CpG oligonucleotides), molecules that mobilize and optimize the adaptive immune system, other molecules that activate or upregulate the action of cytotoxic T lymphocytes, NK cells and helper T cells, and other molecules that inactivate or downregulate suppressor or regulatory T cells.

[0330] The additional therapeutic agent is selected based on the condition, disorder, or disease being treated, for example, the compounds of the invention are co-administered with one or more additional agents that function to enhance or promote the immune response, or to reduce or inhibit the immune response.

[0331] chemotherapy drugs In some embodiments, the compounds of the present invention can be combined with one or more chemotherapeutic or pro-apoptotic agents. Representative chemotherapeutic agents include amsacrine, bleomycin, busulfan, capecitabine, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clofarabine, crisantaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, docetaxel, doxorubicin, epirubicin, etoposide, fludarabine, fluorouracil, gemcitabine, hydroxycarboxamide, idarubicin, ifosfamide, irinotecan, leucovorin, liposomal doxorubicin, Representative pro-apoptotic agents include, but are not limited to, liposomal daunorubicin, lomustine, melphalan, mercaptopurine, mesna, methotrexate, mitomycin, mitoxantrone, oxaliplatin, paclitaxel, pemetrexed, pentostatin, procarbazine, raltitrexed, satraplatin, streptozocin, tegafur-uracil, temozolomide, teniposide, thiotepa, thioguanine, topotecan, treosulfan, vinblastine, vincristine, vindesine, vinorelbine, or combinations thereof. Representative pro-apoptotic agents include, but are not limited to, fludarabine, staurosporine, cycloheximide, actinomycin D, lactosylceramide, 15d-PGJ(2), and combinations thereof.

[0332] anti-inflammatory agents Other suitable additional therapeutic agents include, but are not limited to, anti-inflammatory agents. In some embodiments, the anti-inflammatory agent can be non-steroidal, steroidal, or a combination thereof. Some embodiments provide oral compositions comprising about 1% (w / w) to about 5% (w / w), typically about 2.5% (w / w), of an anti-inflammatory agent. Representative examples of non-steroidal anti-inflammatory drugs are oxicams such as piroxicam, isoxicam, tenoxicam, sudoxicam; salicylates such as aspirin, disalcid, benorylate, trilisate, safapirin, solprin, diflunisal and fendosal; acetic acid derivatives such as diclofenac, fenclofenac, indomethacin, sulindac, tolmetin, isoxepac, furofenac, tiopinac, zidometacin, acemetacin, fentiazac, zomepirac, clindanac, oxepinac, felbinac and ketorolac; fenamates such as mefenam , meclofenam, flufenam, niflum, and tolfenamic acid; propionic acid derivatives such as ibuprofen, naproxen, benoxaprofen, flurbiprofen, ketoprofen, fenoprofen, fenbufen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, and tiaprofen; pyrazoles such as phenylbutazone, oxyphenbutazone, feprazone, azapropazone, and trimethasone. In some embodiments, mixtures of these nonsteroidal anti-inflammatory drugs may also be used.

[0333] Representative examples of steroidal anti-inflammatory drugs include corticosteroids such as hydrocortisone, hydroxyl-triamcinolone, alpha-methyldexamethasone, dexamethasone phosphate, beclomethasone dipropionate, clobetasol valerate, desonide, desoximetasone, desoxycorticosterone acetate, dexamethasone, dichlorisone, diflorasone diacetate, diflucortolone valerate, fluadrenolone, fluchlorone acetonide, fludrocortisone, flumethasone pivalate, fluocinolone acetonide, fluocinonide, flucortine butyl ester, fluocortolone, fluprednidene (fluprednylidene) acetate, flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone, triamcinolone acetonide nido, cortisone, cortodoxone, flucetonide, fludrocortisone, diflorasone diacetate, fluradrenolon, fludrocortisone, diflorasone diacetate, fluradrenolon acetonide, medrysone, amcinafide, amcinafide, betamethasone and its ester balance, chloroprednisone, chloroprednisone acetate, clocortolone, clescinolone, dichlorisone, difluprednate, flucloronide, flunisolide, fluoromethalone, fluperolone, fluprednisolone, hydrocortisone valerate, hydrocortisone cyclopentylpropionate, hydrocortamate, meprednisone, paramethasone, prednisolone, prednisone, beclomethasone dipropionate, triamcinolone and mixtures thereof.

[0334] immunosuppressants In some embodiments, the compounds disclosed herein reduce Treg activity or production. In some embodiments, the compounds disclosed herein are used in induction therapy for cancer. In some embodiments, the compounds disclosed herein are used in combination with other immunotherapeutic agents, immune modulators, costimulatory activating agonists, other cytokines and chemokines and factors, vaccines, oncolytic viruses, cell therapy, small molecule and targeted therapy, chemotherapy, and radiation therapy. In some embodiments, immune modulators include checkpoint inhibitors such as anti-PD1, anti-CTLA4, anti-TIM3, and anti-LAG3. In some embodiments, costimulatory activating agonists include anti-OX40, anti-GITR, and the like. In some embodiments, cell therapy includes engineered T cells, CAR-T, TCR-T cells, and the like.

[0335] In some embodiments, the compounds disclosed herein are used in combination with other immunotherapeutic agents, immune modulators, biologics (e.g., antibodies), vaccines, small molecule and targeted therapies, anti-inflammatory, cell therapies (e.g., engineered Tregs and other types of cells), chemotherapy, and radiation therapy.

[0336] In some embodiments, the compounds disclosed herein, alone or in combination with other agents, are administered to a patient in vivo by intravenous, intramuscular, or other parenteral means. They can also be administered intranasally, by inhalation, rectally, vaginally, topically, orally, or by implant. In other embodiments, the compounds disclosed herein, alone or in combination with other agents, are applied ex vivo to enhance the function of suppressive Tregs, including natural Tregs, inducible Tregs, engineered Tregs, and other types of suppressive T cells, which can then be used to treat a patient, if desired.

[0337] In certain embodiments, the additional therapeutic agent is an immunosuppressant. The immunosuppressant may be an antibody against another lymphocyte surface marker (e.g., CD40, alpha-4 integrin) or cytokine, a fusion protein (e.g., CTLA-4-Ig (Orencia) (登録商標)), TNFR-Ig (Enbrel (登録商標) )), TNF-α blockers, such as Enbrel, Remicade, Cimzia, and Humira, cyclophosphamide (“CTX”) (e.g., Endoxan (登録商標) , Cytoxan (登録商標) , Neosar (登録商標) , Procytox (登録商標) and Revimmune TM ), methotrexate (“MTX”) (e.g., Rheumatrex (登録商標) and Trexall (登録商標) ), belimumab (e.g., Benlysta (登録商標) ), other immunosuppressive drugs (e.g., cyclosporin A, FK506-like compounds, rapamycin compounds, and steroids), antiproliferative agents, cytotoxic agents, and other compounds that may aid in immunosuppression.

[0338] In some embodiments, the additional therapeutic agent may be a checkpoint inhibitor. In some embodiments, the additional therapeutic agent may be a CTLA-4 fusion protein, such as CTLA-4-Ig (abatacept). CTLA-4-Ig fusion proteins compete with the T cell costimulatory receptor, CD28, for binding to CD80 / CD86 (B7-1 / B7-2) on antigen-presenting cells, and thus may function to inhibit T cell activation. In other embodiments, the additional therapeutic agent is the CTLA-4-Ig fusion protein known as belatacept. Belatacept contains two amino acid substitutions (L104E and A29Y) that may significantly increase its avidity for CD86 in vivo. In other embodiments, the additional therapeutic agent is Maxy-4.

[0339] In other embodiments, the additional therapeutic agent is CTX. (登録商標) , Cytoxan (登録商標) , Neosar (登録商標) , Procytox (登録商標) and Revimmune TMCTX (generic name), also known as cytophosphan, is a nitrogen mustard alkylating agent of the oxazophorin group. It can be used to treat various types of cancer and some autoimmune disorders. CTX is the primary drug used to treat disseminated proliferative glomerulonephritis in patients with renal lupus.

[0340] In certain embodiments, an additional therapeutic agent may be administered to a patient in need thereof in an amount effective to reduce blood or serum levels of anti-double stranded DNA ("anti-ds DNA") autoantibodies and / or reduce proteinuria.

[0341] In other embodiments, the additional therapeutic agent can increase the amount of adenosine in serum (see, e.g., WO08 / 147482). For example, the second therapeutic agent can be CD73-Ig, recombinant CD73, or other agents (e.g., cytokines, monoclonal antibodies, or small molecules) that increase the expression of CD73 (see, e.g., WO04 / 084933). In other embodiments, the additional therapeutic agent is interferon-beta.

[0342] In certain embodiments, the additional therapeutic agent can be a small molecule that inhibits or reduces differentiation, proliferation, activity, cytokine production and / or cytokine secretion by Th1, Th17, Th22 and / or other cells that secrete, or cause other cells to secrete, proinflammatory molecules, including, but not limited to, IL-1β, TNF-α, TGF-beta, IFN-γ, IL-18, IL-17, IL-6, IL-23, IL-22, IL-21, and MMPs. In other embodiments, the additional therapeutic agent is a small molecule that interacts with Tregs, enhances Treg activity, promotes or enhances IL-10 secretion by Tregs, increases Treg numbers, increases the suppressive capacity of Tregs, or a combination thereof.

[0343] In some embodiments, the composition increases Treg activity or production. Examples of Treg enhancers include, but are not limited to, glucocorticoid fluticasone, salmeterol, antibodies against IL-12, IFN-γ, and IL-4; vitamin D3 and dexamethasone, and combinations thereof.

[0344] In certain embodiments, the additional therapeutic agent is an antibody, e.g., a function-blocking antibody, against a pro-inflammatory molecule such as IL-6, IL-23, IL-22, or IL-21.

[0345] In some embodiments, the additional therapeutic agent comprises a nucleic acid. In some embodiments, the additional therapeutic agent comprises a ribonucleic acid.

[0346] Combination Treatment of Neurodegenerative Diseases In some embodiments, the compounds disclosed herein can be administered with a second treatment selected based on the subject's disease state.In some embodiments, the second treatment can be a treatment for Alzheimer's disease.Current treatments for Alzheimer's disease include, but are not limited to, cholinesterase inhibitors, such as donepezil, rivastigmine and galantamine; memantine; antidepressants, such as citalopram, fluoxetine, paroxetine, sertraline and trazodone; antianxiety drugs, such as lorazepam and oxazepam; and antipsychotics, such as aripiprazole, clozapine, haloperidol, olanzapine, quetiapine, risperidone and ziprasidone.

[0347] In other embodiments, the additional therapeutic agent may be for the treatment of ALS. There are currently two US FDA-approved treatments for ALS: riluzole and edaravone. Both drugs have been shown to slow the progression of ALS. In addition to riluzole and edaravone, subjects with ALS can also be treated with drugs that target specific symptoms of the disease. Examples of such drugs include, but are not limited to, drugs that reduce spasticity, such as antispasmodics (e.g., baclofen, dantrolene, and diazepam); drugs that help manage nerve pain, such as amitriptyline, carbamazepine, duloxetine, gabapentin, lamotrigine, milnacipran, nortriptyline, pregabalin, and venlafaxine; and drugs that help patients swallow, such as trihexyphenidyl or amitriptyline.

[0348] In some embodiments, the additional therapeutic agent can be for the treatment of Parkinson's disease.The current treatment of Parkinson's disease includes but is not limited to: carbidopa-levodopa; dopamine agonist such as pramipexole, ropinirole and rotigotine; MAO B inhibitor such as selegiline, rasagiline and safinamide; catechol O-methyltransferase inhibitor such as entacapone and tolcapone; anticholinergic agent such as benztropine and trihexyphenidyl; and amantadine.

[0349] In some embodiments, the second therapeutic agent can be for the treatment of Huntington's disease. Current treatments for Huntington's disease include, but are not limited to, tetrabenazine; antipsychotics such as haloperidol, chlorpromazine, risperidone, and quetiapine; amantadine; levetiracetam; clonazepam; antidepressants such as citalopram, escitalopram, fluoxetine, and sertraline; and anticonvulsants such as valproate, carbamazepine, and lamotrigine.

[0350] Combination Treatments for Weight Loss In some embodiments, the compounds disclosed herein can be administered to subjects with other therapeutic agents used to treat cachexia or extreme weight loss.The current strategy for treating cachexia and extreme weight loss is to improve appetite by using appetite stimulants to ensure adequate nutritional intake.Pharmacological intervention with appetite stimulants, nutritional supplementation, 5-HT3 antagonists and Cox-2 inhibitors is used to treat cancer cachexia.

[0351] In some embodiments, the appetite stimulant is a vitamin, mineral, or herb, including, but not limited to, zinc, thiamine, or fish oil, hi other embodiments, the appetite stimulant is a medication, including, but not limited to, dronabinol, megestrol, and oxandrolone.

[0352] equivalent The following representative examples are intended to aid in the explanation of the present invention and are not intended to, and should not be construed as, limiting the scope of the present invention. Indeed, various modifications of the present invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the entire contents of this document, including the following examples and the scientific and patent literature cited herein. Furthermore, the contents of the cited references are incorporated herein by reference to help describe the state of the art. The following examples contain important additional information, exemplification and guidance that can be adapted to the practice of this invention in its various embodiments and equivalents. [Example]

[0353] Example 1: Compound 1 (3-((6-nitroquinolin-4-yl)amino)-N-(3-(pyridin-4-ylamino)phenyl)benzamide) [ka] As shown in Scheme 1, meta-nitrobenzoic acid was coupled with 1,3-phenylenediamine using EDCI in the presence of HOBt and DIPEA. The resulting intermediate was coupled with 4-chloropyridine, followed by reduction of the nitro group to an amino group using Sn / HCl. The resulting amino intermediate was then refluxed for 3 hours in 4-chloro-6-nitroquinoline and EtOH with 2-3 drops of TEA to afford the meta-substituted product, Compound 1. The final product precipitated from the reaction mixture upon reaching room temperature and was then collected by filtration and purified by recrystallization from 1:1 EtOH:diethyl ether.

[0354] The compounds set forth in the following examples were prepared in an analogous manner based on the procedures described in Example 1 and / or as described below and / or by methods known in the art.

[0355] The following abbreviations used in the following examples have the following definitions: DCE = dichloroethane; DCM = dichloromethane; DIEPA or DIPEA = N,N-diisopropylethylamine; DMAP = 4-dimethylaminopyridine; DMF = dimethylformamide; EA or EtOAc = ethyl acetate; EDC or EDCI = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; HPLC = high performance liquid chromatography; PE = petroleum ether; RT = retention time (e.g., HPLC retention time); TEA = triethylamine; TFA = trifluoroacetic acid; THF = tetrahydrofuran; and TsOH or TosOH = p-toluenesulfonic acid. These abbreviations and definitions are not intended to limit other abbreviations and definitions herein.

[0356] Example 2: Compound 2 (3-((6-cyanoquinolin-4-yl)amino)-N-(4-(pyridin-4-ylamino)phenyl)benzamide) [ka] Compound 2 was prepared by methods known in the art and / or methods analogous to those described herein. Compound 2 (3-((6-cyanoquinolin-4-yl)amino)-N-(4-(pyridin-4-ylamino)phenyl)benzamide): C 28 H 20 N6O;456.51g / mol;26mg;yellow solid;ESI-LCMS m / z=457 [M+H] + ;LCMS RT=1.594 min, 100% (214 nm).

[0357] Example 3: Compound 3 (3-((6-fluoroquinolin-4-yl)amino)-N-(4-(pyridin-4-ylamino)phenyl)benzamide) [ka] Compound 3 was prepared by methods known in the art and / or methods analogous to those described herein. Compound 3 (3-((6-fluoroquinolin-4-yl)amino)-N-(4-(pyridin-4-ylamino)phenyl)benzamide): C 27 H 20 FN5O;449.49g / mol;34mg;white solid;ESI-LCMS m / z=450 [M+H] + ;LCMS RT=1.614 min, 99% (214 nm).

[0358] Example 4: Compound 4 (4-((3-(6-(pyridin-4-ylamino)-1H-benzo[d]imidazol-2-yl)phenyl)amino)quinoline-6-carbonitrile) [ka] Compound 4 was prepared by methods known in the art and / or methods analogous to those described herein. Compound 4 (4-((3-(6-(pyridin-4-ylamino)-1H-benzo[d]imidazol-2-yl)phenyl)amino)quinoline-6-carbonitrile): C 28 H 19 N7;453.51g / mol;22mg;yellow solid;ESI-LCMS m / z=454 [M+H]+ ;LCMS RT=1.634 min, 100% (214 nm).

[0359] Example 5: Compound 5 (3-((6-fluoroquinolin-4-yl)amino)-N-(4-(pyridin-4-yloxy)phenyl)benzamide) [ka] [ka] Compound 5 was prepared by the method shown in Scheme 2. Compound 5 (3-((6-fluoroquinolin-4-yl)amino)-N-(4-(pyridin-4-yloxy)phenyl)benzamide) was prepared as shown in Scheme 2: 27 H 19 FN4O2;450.47g / mol;13mg;white solid;ESI-LCMS m / z=451 [M+H] + ;LCMS RT=0.99 min, >95.00%(214nm).

[0360] Example 6: Compound 6 (3-((6-fluoroquinolin-4-yl)amino)-N-(4-((2-methylpyridin-4-yl)oxy)phenyl)benzamide) [ka] Compound 6 was prepared by methods known in the art and / or methods analogous to those described herein. Compound 6 (3-((6-fluoroquinolin-4-yl)amino)-N-(4-((2-methylpyridin-4-yl)oxy)phenyl)benzamide): C 28 H 21 FN4O2;464.50g / mol;18mg;light yellow solid;ESI-LCMS m / z=456 [M+H] + ;LCMS RT=1.43 min, >95.00%(214nm).

[0361] Example 7: Compound 7 (4-((6-fluoroquinolin-4-yl)amino)-N-(3-phenoxyphenyl)benzamide) [ka] Compound 7 was prepared by methods known in the art and / or methods analogous to those described herein. Compound 7 (4-((6-fluoroquinolin-4-yl)amino)-N-(3-phenoxyphenyl)benzamide): C 28 H 20 FN3O2;449.49g / mol;13mg;white solid;ESI-LCMS m / z=450 [M+H] + ;LCMS RT=1.74 min, >95.00%(214nm).

[0362] Example 8: Compound 8 (3-(pyridin-4-ylamino)-N-(4-(pyridin-4-ylamino)phenyl)benzamide) [ka] [ka] Compound 8 was prepared by the method shown in Scheme 3. Compound 8 (3-(pyridin-4-ylamino)-N-(4-(pyridin-4-ylamino)phenyl)benzamide) was prepared as shown in Scheme 3: C 23 H 19 N5O;381.44g / mol;12mg;pale yellow solid;ESI-LCMS m / z=382 [M+H] + ;LCMS RT=1.30 min, >95.00%(214nm).

[0363] Example 9: Compound 9 (N-(4-(pyridin-4-ylamino)phenyl)-3-(quinolin-4-ylamino)benzamide) [ka] [ka] Compound 9 was prepared by the method shown in Scheme 4. Compound 9 (N-(4-(pyridin-4-ylamino)phenyl)-3-(quinolin-4-ylamino)benzamide) was prepared as shown in Scheme 4: 27 H 21 N5O;431.50g / mol;24mg;pale yellow solid;ESI-LCMS m / z=432 [M+H] + ;LCMS RT=1.46 min, >95.00%(214nm). Example 10: Compound 10 (N-(4-(pyridin-4-yloxy)phenyl)-3-(quinolin-4-ylamino)benzamide) [ka] [ka]

[0364] Compound 10 was prepared by the method shown in Scheme 5. Compound 10 (N-(4-(pyridin-4-yloxy)phenyl)-3-(quinolin-4-ylamino)benzamide) was prepared as shown in Scheme 5: 27 H 20 N4O2;432.48g / mol;29mg;light yellow solid;ESI-LCMS m / z=433 [M+H] + ;LCMS RT=1.43 min, >95.00%(214nm).

[0365] Example 11: Compound 11 (3-((2-methylpyridin-4-yl)amino)-N-(4-(pyridin-4-ylamino)phenyl)benzamide) [ka] [ka] Compound 11 was prepared by the method shown in Scheme 6. Compound 11 (3-((2-methylpyridin-4-yl)amino)-N-(4-(pyridin-4-ylamino)phenyl)benzamide) was prepared as shown in Scheme 6:24 H 21 N5O;395.47g / mol;16mg;pale yellow solid;ESI-LCMS m / z=396 [M+H] + ;LCMS RT=1.32 min, >95.00%(214nm). Example 12: Compound 12 (3-((3-methylquinolin-4-yl)amino)-N-(4-(pyridin-4-ylamino)phenyl)benzamide) [ka] [ka]

[0366] Compound 12 was prepared by the method shown in Scheme 7. Compound 12 (3-((3-methylquinolin-4-yl)amino)-N-(4-(pyridin-4-ylamino)phenyl)benzamide) was prepared as shown in Scheme 7: 28 H 23 N5O;445.53g / mol;19mg;pale yellow solid;ESI-LCMS m / z=446 [M+H] + ;LCMS RT=1.48 min, >95.00%(214nm).

[0367] Example 13: Compound 13 (3-((2-methylquinolin-4-yl)amino)-N-(4-(pyridin-4-ylamino)phenyl)benzamide) [ka] [ka] Compound 13 was prepared by the method shown in Scheme 8. Compound 13 (3-((2-methylquinolin-4-yl)amino)-N-(4-(pyridin-4-ylamino)phenyl)benzamide) was prepared as shown in Scheme 8: 28 H 23 N5O;445.53g / mol;20mg;pale yellow solid;ESI-LCMS m / z=446 [M+H] +;LCMS RT=1.46 min, >95.00%(214nm).

[0368] Example 14: Compound 14 (3-((8-methylquinolin-4-yl)amino)-N-(4-(pyridin-4-ylamino)phenyl)benzamide) [ka] [ka] Compound 14 was prepared by the method shown in Scheme 9. Compound 14 (3-((8-methylquinolin-4-yl)amino)-N-(4-(pyridin-4-ylamino)phenyl)benzamide) was prepared as shown in Scheme 9: 28 H 23 N5O;445.53g / mol;29mg;pale yellow solid;ESI-LCMS m / z=446 [M+H] + ;LCMS RT=1.54 min, >95.00%(214nm).

[0369] Example 15: Compound 15 (3-((7-methylquinolin-4-yl)amino)-N-(4-(pyridin-4-ylamino)phenyl)benzamide) [ka] [ka] Compound 15 was prepared by the method shown in Scheme 10. Compound 15 (3-((7-methylquinolin-4-yl)amino)-N-(4-(pyridin-4-ylamino)phenyl)benzamide) was prepared as shown in Scheme 10: 28 H 23 N5O;445.53g / mol;24mg;pale yellow solid;ESI-LCMS m / z=446 [M+H] + ;LCMS RT=1.48 min, >95.00%(214nm).

[0370] Example 16: Compound 16 (3-((5-methylquinolin-4-yl)amino)-N-(4-(pyridin-4-ylamino)phenyl)benzamide) [ka] [ka] Compound 16 was prepared by the method shown in Scheme 11. Compound 16 (3-((5-methylquinolin-4-yl)amino)-N-(4-(pyridin-4-ylamino)phenyl)benzamide) was prepared as shown in Scheme 11: 28 H 23 N5O;445.53g / mol;17mg;pale yellow solid;ESI-LCMS m / z=446 [M+H] + ;LCMS RT=1.49 min, >95.00%(214nm).

[0371] Example 17: Compound 17 (4-((3-(5-(pyridin-4-ylamino)-3H-imidazo[4,5-b]pyridin-2-yl)phenyl)amino)quinoline-6-carbonitrile) [ka] [ka] Compound 17 was prepared by the method shown in Scheme 12. Compound 17 (4-((3-(5-(pyridin-4-ylamino)-3H-imidazo[4,5-b]pyridin-2-yl)phenyl)amino)quinoline-6-carbonitrile) was prepared as shown in Scheme 12; C 27 H 18 N8;454.50g / mol;13mg;yellow solid;ESI-LCMS m / z=455 [M+H] + ;RT=1.44min, >95.00%(214nm).

[0372] Example 18: Compound 18 (3-((5-methylquinolin-4-yl)amino)-N-(4-(pyridin-4-ylamino)phenyl)benzamide) [ka] [ka] Process a To a stirred mixture of compound 18-1 (20 g, 0.1 mol) in 1,4-dioxane (500 mL) under nitrogen, pyridin-4-amine (compound 18-2) (9.4 g, 0.1 mol), Cs2CO3 (65 g, 0.2 mol), Pd2(dba)3 (457 mg, 0.5 mmol), and Xantphos (457 mg, 0.8 mmol) were added. The resulting mixture was stirred at 100 °C for 2 h. The reaction was then quenched with water (500 mL) and extracted with EA (3 × 500 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (0–50% EA in PE) to give compound 18-3 (19.8 g, 93%) as a yellow solid.

[0373] Process b To a mixture of compound 18-3 (19.8 g, 93 mmol) in MeOH (1000 mL) was added Pd / C (986 mg, 0.93 mmol), and the mixture was stirred under H at room temperature for 4 h. The combined organic phase was filtered through diatomaceous earth to give compound 18-4 as a yellow solid (16.9 g, 98.5%).

[0374] Process c To a mixture of compound 18-4 (16.9 g, 92 mmol) in DMF (250 mL) was added 3-((tert-butoxycarbonyl)amino)benzoic acid (compound 18-5) (21.8 g, 92 mmol), EDCI (9.1 mg, 0.01 mmol), and DMAP (22.4 g, 184 mmol), and the mixture was stirred at room temperature for 16 h. The reaction was then quenched with water (1000 mL) and extracted with EA (3 × 600 mL). The combined organic phases were dried over NaSO, filtered, and concentrated. The residue was purified by flash silica gel chromatography (0–50% EA in PE) to give compound 18-6 (30.2 g, 81.2%) as a white solid.

[0375] Process d A mixture of compound 18-6 (30.2 g, 74 mmol) in dioxane hydrochloride (1000 mL, 4 M) was stirred at room temperature for 4 h. The combined organic phase was concentrated to give compound 18-7 as a white solid (20.2 g, 90%).

[0376] Process e To a mixture of compound 18-7 (50 mg, 0.16 mmol) in DMSO (2 mL) was added DMSO (2 mL). The mixture was stirred at 100° C. for 1 hour. The crude residue was purified by preparative HPLC to give compound 18 (3-((5-methylquinolin-4-yl)amino)-N-(4-(pyridin-4-ylamino)phenyl)benzamide) as a pale yellow solid (11 mg, 15.0%): C 28 H 23 N5O;445.53g / mol;ESI-LCMS m / z=446 [M+H] + ;RT=1.49min, >95.00%(214nm).

[0377] Example 19: Compound 19 (4-(2-aminopyridin-4-ylamino)-N-(3-(pyridin-4-ylamino)phenyl)benzamide) [ka] [ka] Process aTo a stirred mixture of 1-bromo-3-nitrobenzene (compound 19-1) (20 g, 0.1 mol) in 1,4-dioxane (500 mL) under a nitrogen atmosphere, pyridin-4-amine (compound 18-2) (9.4 g, 0.1 mol), CsCO (65 g, 0.2 mol), Pd(dba) (457 mg, 0.5 mmol), and Xantphos (457 mg, 0.8 mmol) were added. The resulting mixture was stirred at 100 °C for 2 h. The reaction was then quenched with water (500 mL) and extracted with EA (3 × 500 mL). The combined organic phases were dried over NaSO, filtered, and concentrated. The residue was purified by flash silica gel chromatography (0–50% EA in PE) to give compound 19-2 (20 g, 93%) as a yellow solid.

[0378] Process b To a mixture of compound 19-2 (20 g, 93 mmol) in MeOH (1000 mL) was added Pd / C (986 mg, 0.93 mmol), and the mixture was stirred under H at room temperature for 4 h. The combined organic phase was filtered through diatomaceous earth to give compound 19-3 as a yellow solid (17.0 g, 98.7%).

[0379] Process c To a mixture of compound 19-3 (17.0 g, 92 mmol) in DMF (250 mL) was added 4-((tert-butoxycarbonyl)amino)benzoic acid (compound 19-4) (21.8 g, 92 mmol), EDCI (9.1 mg, 0.01 mmol), and DMAP (22.4 g, 184 mmol), and the mixture was stirred at room temperature for 16 h. The reaction was then quenched with water (1000 mL) and extracted with EA (3 × 600 mL). The combined organic phases were dried over NaSO, filtered, and concentrated. The residue was purified by flash silica gel chromatography (0–50% EA in PE) to give compound 19-5 (30 g, 81%) as a white solid.

[0380] Process dA mixture of compound 19-5 (30 g, 74 mmol) in dioxane hydrochloride (1000 mL, 4 M) was stirred at room temperature for 4 h. The combined organic phase was concentrated to give compound 19-6 as a white solid (20.2 g, 90%).

[0381] Process e To a mixture of compound 19-6 (50 mg, 0.164 mmol) in 1,4-dioxane (2 mL), tert-butyl (4-bromopyridin-2-yl)carbamate (compound 19-7) (45 mg, 0.164 mmol), Pd(dba) (9.1 mg, 0.01 mmol), Xantphos (6 mg, 0.01 mmol), and CsCO (102 mg, 0.32 mmol) were added, and the mixture was stirred under N at 100 °C for 12 h. The mixture was concentrated to give compound 19-8, which was used directly in the next step without further purification.

[0382] Process f A solution of compound 19-8 in TFA (3 mL) was stirred at room temperature for 1 hour. The mixture was concentrated, and the crude residue was purified by preparative HPLC to give compound 19 (4-(2-aminopyridin-4-ylamino)-N-(3-(pyridin-4-ylamino)phenyl)benzamide) as a white solid (12 mg, 18.5%): C 23 H 20 N6O;396.44g / mol;ESI-LCMS m / z=397 [M+H] + ;RT=1.44min, >95.00%(214nm).

[0383] Example 20: Compound 20 (4-(2-amino-6-methylpyridin-4-ylamino)-N-(3-(pyridin-4-ylamino)phenyl)benzamide) [ka] [ka] Compound 19-6 was prepared in a manner similar to that described in Example 19.

[0384] Process a To a mixture of compound 19-6 (50 mg, 0.164 mmol) in 1,4-dioxane (2 mL), tert-butyl (4-bromopyridin-2-yl)carbamate (compound 20-1) (45 mg, 0.164 mmol), Pd(dba) (9.1 mg, 0.01 mmol), Xantphos (6 mg, 0.01 mmol), and CsCO (102 mg, 0.32 mmol) were added, and the mixture was stirred under N at 100 °C for 12 h. The mixture was concentrated to give compound 20-2, which was used directly in the next step without further purification.

[0385] Process b A solution of compound 20-2 in TFA (3 mL) was stirred at room temperature for 1 hour. The mixture was concentrated, and the crude residue was purified by preparative HPLC to give compound 20 (4-(2-amino-6-methylpyridin-4-ylamino)-N-(3-(pyridin-4-ylamino)phenyl)benzamide) as a white solid (12 mg, 18.5%): C 24 H 22 N6O;410.47g / mol;ESI-LCMS m / z=411 [M+H] + ;RT=1.47min, >95.00%(214nm).

[0386] Example 21: Compound 21 (4-(2-amino-3-methylpyridin-4-ylamino)-N-(3-(pyridin-4-ylamino)phenyl)benzamide) [ka] [ka] Compound 19-6 was prepared in a manner similar to that described in Example 19.

[0387] Process aTo a mixture of compound 19-6 (50 mg, 0.164 mmol) in 1,4-dioxane (2 mL), compound 21-1 (45 mg, 0.164 mmol), Pd(dba) (9.1 mg, 0.01 mmol), Xantphos (6 mg, 0.01 mmol), and CsCO (102 mg, 0.32 mmol) were added, and the mixture was stirred at 100 °C under N for 12 h. The mixture was concentrated to give compound 20-2, which was used directly in the next step without further purification.

[0388] Process b A solution of compound 21-2 in TFA (3 mL) was stirred at room temperature for 1 hour. The mixture was concentrated, and the crude residue was purified by preparative HPLC to give compound 21 (4-(2-amino-3-methylpyridin-4-ylamino)-N-(3-(pyridin-4-ylamino)phenyl)benzamide) as a white solid (12 mg, 18.5%): C 24 H 22 N6O;410.47g / mol;ESI-LCMS m / z=411 [M+H] + ;RT=1.42min, >95.00%(214nm).

[0389] Example 22: Compound 22 (4-((2-(4-(pyridin-4-ylamino)phenyl)-1H-benzo[d]imidazol-5-yl)amino)quinoline-6-carbonitrile) [ka] [ka] Compound 22 was prepared by the method shown in Scheme 17. Compound 22 (4-((2-(4-(pyridin-4-ylamino)phenyl)-1H-benzo[d]imidazol-5-yl)amino)quinoline-6-carbonitrile) was prepared as shown in Scheme 32: 28 H 19 N7;453.51g / mol;11mg;Pale yellow solid;ESI-LCMS m / z=454 [M+H] + ;LCMS RT=1.35 min, >95.00%(214nm).

[0390] Example 23. Biological Assays Foxp3 induction assay CD4+ conventional T cells (Tconvs-CD4+ / CD25) sorted or enriched (Miltenyi magnetic separation) from C57 / Bl6 mice were used for iTreg induction. 10 μg / mL plate-bound anti-CD3 antibody (50 μl / well of a 96-well plate), 2.5 μg / mL soluble anti-CD28 antibody, 100 IU / mL IL2, and 5 ng / mL TGF-β were used in the absence or presence of various drug concentrations (usually titrated from 0.01 μM to 10 μM). A TGF-β-free sample was used as a negative control for induction.

[0391] After 3 days of culture in the presence of stimuli, TGF-β, and drugs, cells were stained with a fixative live / dead cell stain (Life Technologies, NY) for gating and toxic dose exclusion. Cells were fixed and permeabilized using a mouse Foxp3 buffer kit (BD Bioscience, San Jose, CA) according to the manufacturer's instructions. Anti-CD4 and anti-Foxp3 antibodies were used to stain the cells. After staining, cells were acquired using a flow cytometer.

[0392] Jurkat-FoxP3 reporter assay (BPS Bioscience, Cat # 60628) Cell culture process: Prepare a 50 ml conical tube and a T-25 culture flask containing 5 ml of prewarmed Thaw Medium 2 (without G418). Thaw the cells quickly in a 37°C water bath with constant, slow agitation. Transfer the entire contents to a conical tube containing Thaw Medium 2 (without G418) and centrifuge the cells at 200 x g for 3 minutes. Resuspend the cells in 6 ml of prewarmed Thaw Medium 2 (without G418) and transfer the entire contents to a T25 culture flask containing Thaw Medium 2 (without G418). Incubate the cells in a humidified 37°C incubator with 5% CO2. After 48 hours of incubation, centrifuge the cells at 250 x g for 5 minutes and resuspend them in fresh Thaw Medium 2 (without G418). Continue to monitor growth for 2–3 days, replacing cells to remove dead debris. Once multiple cell colonies (clumps) begin to appear (an indication of healthy cell division), switch to Growth Medium 2B (containing G418).

[0393] Post-assay protocol: (CD3 / CD28) 1. Jurkat-FoxP3-luciferase reporter cells were cultured in white opaque 384-well plates at approximately 2.5 x 103 cells / well (10 μL / well) in assay medium (RPMI 1640 medium (Thermo Fisher, Cat. No. A1049101) supplemented with 1% penicillin / streptomycin) in the absence and presence of human T-activator CD3 / CD28 Dynabeads (Thermo Fisher, Cat. No. 11161D) at a ratio of 1:5.

[0394] 2. Drugs are serially diluted over a range of 1-60,000 nM, and 10 μL of drug is added to give a range of 1-30,000 nM, vortexing with gentle sacking. In some experiments, the range was 10-20,000 nM. Cells are cultured in the presence and absence of drug for 12 hours at 37°C in 5% CO2.

[0395] 3. ONE-Step TMAdd Luciferase Assay System (BPS Bioscience, Cat. #60690) to each well according to the protocol. Add an equal volume of luciferase assay working solution (Component A + Component B) to the culture medium in each well. As an example, a 384-well plate containing 20 μl of culture medium per well requires 20 μl of luciferase assay working solution.

[0396] 4. Gently rock the plate for ≥ 15 minutes at room temperature. Measure firefly luminescence using a luminometer.

[0397] Phospho-Akt isoform specificity assay Human CD4+ / CD45R a Naive CD25+ T cells were plated for 72 hours under induction conditions (IL-2 / anti-CD3 / anti-CD28+TGFβ) in the absence or presence of compounds. To determine compound specificity for each phospho-AKT isoform, a phospho-AKT cell HTRF kit (Cisbio catalog numbers 63ADK078PEG(pAKT1), 63ADK080PEG(p-AKT2), ​​and 63ADK082PEG(pAKT3)) was used according to the manufacturer's instructions. Briefly, after removing the supernatant for all samples, cells were lysed, and total protein concentration was measured and normalized. Cell lysates were transferred to 384-well plates and a Eu cryptate antibody + d2 antibody mixture was added. This process was the same for each isoform, except that the corresponding isoform antibody from each kit was used. Positive and negative controls (packaged with the kit) were included in each experiment. Plates were incubated overnight. Data were acquired using a Varioskan Lux reader set up with the TRF fluorescence protocol. Data were expressed as percent change relative to DMSO-treated controls. Each test condition was performed in duplicate, and assays were performed at least twice.

[0398] IL-10 ELISA assay Human CD4+ / CD25+ natural Treg cells were seeded under stimulation conditions (IL-2 / anti-CD3 / anti-CD28) in the absence or presence of compounds. After 24 and 48 hours of incubation, supernatants were collected, and IL-10 concentrations were determined using a human IL-10 ELISA kit (Invitrogen BMS215-2) according to the manufacturer's specifications. Briefly, supernatants were added to precoated 96-well ELISA plates and incubated, followed by the addition of a biotin-conjugated detection antibody and streptavidin-HRP. After incubation, substrate was added, and the reaction was stopped by the addition of acid. Absorbance was measured at 450 nm using a Varioskan Lux reader. A calibration curve was generated using known concentrations of IL-10 (provided in the kit), and the IL-10 concentration in the supernatants was calculated. Data were expressed as a percent change relative to the untreated stimulated cell control. Each test condition was performed in triplicate, and the assay was performed at least twice.

[0399] FoxP3 ELISA assay Human CD4+ / CD45R a Naive CD25+ / CD25 T cells were plated under induction conditions (IL-2 / anti-CD3 / anti-CD28+TGFβ) in the absence or presence of compound for 72 hours. After incubation, cells were lysed, and FoxP3 protein was measured in the lysates using a human FoxP3 ELISA kit (LSBio, LS-F5047) according to the manufacturer's instructions. Briefly, lysates were added to precoated 96-well ELISA plates and incubated, followed by the addition of a biotin-conjugated detection antibody and streptavidin-HRP. After incubation, substrate was added, and the reaction was stopped by adding acid. Absorbance was measured at 450 nm using a Varioskan Lux reader. A calibration curve was generated using known concentrations of FoxP3 (included in the kit), and the FoxP3 concentration in the lysates was calculated. Data are presented as a percent change relative to cell induction in the absence of compound. Each test condition was performed in duplicate, and assays were performed at least twice.

[0400] iTreg induction assay Sorted human CD4 T cells were used to induce iTregs. Human T cell activation beads (Gibco Dynabeads CD3 / CD28), 100 IU / mL IL2, and 5 ng / mL TGF-β were used in the absence or presence of various drug concentrations. A TGF-β-free sample was used as a negative control for induction. After 3 days of TGF-β stimulation and drug-presence culture, cells were stained with a fixative live / dead cell stain (Life Technologies) for gating and toxic dose exclusion, fixed and permeabilized using a Foxp3 buffer kit according to the manufacturer's instructions (BD Bioscience), and stained with an anti-Foxp3 antibody. After staining, cells were acquired using a flow cytometer. Each test condition was performed in duplicate, and assays were performed at least twice.

[0401] Figure 1, obtained at least in part using this assay protocol, shows assessment of iTreg induction (FoxP3) from human CD4 T cells treated with compound 22 in the presence of anti-CD3 / anti-CD28 / IL-2 / TGFβ.

[0402] The Akt3 inhibitory and activating activities of selected compounds disclosed herein are shown in Tables 1 and 2, respectively. [Table 2] [Table 3]

Claims

1. Formula Ia, Ib or Ic 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, Where: 【Chemistry 2】 teeth 【Transformation 3】 and X １ , X ２ , X ３ , X ４ , X ５ , X ６ , X ７ , X ８ and X ９ is independently CR in each case １ or N; R １ H, D, halogen, (C １ -C ６ ) alkyl, (C １ -C ６ ) haloalkyl, (C ２ -C ６ ) alkenyl, (C ２ -C ６ ) haloalkenyl, (C ２ -C ６ ) alkynyl, (C ２ -C ６ ) haloalkynyl, (C ３ -C ７ ) cycloalkyl, (C ４ -C １０ ) bicycloalkyl, (C ３ -C ７ ) heterocycloalkyl, halogenated (C ３ -C ７ ) heterocycloalkyl, (C ４ -C １０ ) heterobicycloalkyl, (C ４ -C １０ ) heterospiroalkyl, aryl, heteroaryl, -OR ａ , -SR ａ , -N(R ａ ) ２ , -COR ａ , -CO ２ R ａ , CON(R ａ ) ２ , -CN, -NC, NO ２ , N ３ , -SO ２ R ａ , -SO ２ N(R ａ ) ２ , -N(R ａ )SO ２ R ａ , 【Chemistry 4】 and optionally one or more (C １ -C ６ ) alkyl, halogenated (C １ -C ６ ) alkyl, -SO ２ R ａ or -SO ２ N(R ａ ) ２ partially saturated bicyclic heteroaryl substituted with Here, R １ (C ３ -C ７ ) cycloalkyl, (C ４ -C １０ ) bicycloalkyl, (C ３ -C ７ ) heterocycloalkyl, (C ４ -C １０ ) heterobicycloalkyl, (C ４ -C １０ ) heterospiroalkyl, aryl and heteroaryl each optionally have one or more (C １ -C ６ ) alkyl, halogenated (C １ -C ６ ) Alkyl, halogen, -OR ａ , —CN or —N(R ａ ) ２ is substituted with; n is an integer from 0 to 4, depending on the valence; Q is C(R ａ ) ２ , O., N.R. ａ , N(C=O)R ａ or NSO ２ R ａ and Y １ , Y ２ , Y ３ , Y ４ and Y ５ are each independently N or CR depending on the valence ２ and R ２ is H, halogen, D, (C １ -C ６ ) alkyl, (C １ -C ６ ) haloalkyl, (C ２ -C ６ ) alkenyl, (C ２ -C ６ ) haloalkenyl, (C ２ -C ６ ) alkynyl, (C ２ -C ６ ) haloalkynyl, (C ３ -C ７ ) cycloalkyl, (C ４ -C １０ ) bicycloalkyl, (C ３ -C ７ ) heterocycloalkyl, halogenated (C ３ -C ７ ) heterocycloalkyl, (C ４ -C １０ ) heterobicycloalkyl, (C ４ -C １０ ) heterospiroalkyl, aryl, heteroaryl, -OR ａ , -SR ａ , -N(R ａ ) ２ , -COR ａ , -CO ２ R ａ , CON(R ａ ) ２ , -CN, -NC, NO ２ , N ３ , -SO ２ R ａ , -SO ２ N(R ａ ) ２ , -N(R ａ )SO ２ R ａ , 【Transformation 5】 selected from the group consisting of: -E-G-は-(C=O)NR ｘ -、-NR ｘ (C=O)-、-N(R ｘ )(C=O)N(R ｘ )-、-O(C=O)N(R ｘ )-、 -N(R ｘ )(C=O)O-,-SO ２ NR ｘ -, -NR ｘ SO ２ -or 【Transformation 6】 where: R ｘ is independently H in each case, (C １ -C ６ ) alkyl, (C ３ -C ７ ) cycloalkyl, aryl, or heteroaryl; or where R ｘ and Y ３ , R ｘ and Y ４ , R ｘ and Z １ or R ｘ and Z ４ together form an optionally substituted 5- to 6-membered heterocycle; W １ , W ２ , W ３ , W ４ and W ５ are each independently valence-enabled CR ６ , N or NR ６ and R ６ is independently in each occurrence H, halogen, (C １ -C ６ ) alkyl and (C １ -C ６ ) haloalkyl; T is independently in each occurrence O, N, NR depending on the valence. ａ , N(C=O)R ａ , NC(R ｂ ) ２ OP(=O)(OR ｂ ) ２ or NSO ２ R ａ and U is independently in each occurrence O, N, NR depending on the valence ａ , N(C=O)R ａ , NC(R ｂ ) ２ OP(=O)(OR ｂ ) ２ or NSO ２ R ａ and R ｂ is independently in each occurrence H or (C １ -C ６ ) alkyl; Z １ , Z ２ , Z ３ , Z ４ and Z ５ are each independently N or CR depending on the valence ３ and R ３ H, D, halogen, (C １ -C ６ ) alkyl, (C １ -C ６ ) haloalkyl, (C ２ -C ６ ) alkenyl, (C ２ -C ６ ) haloalkenyl, (C ２ -C ６ ) alkynyl, (C ２ -C ６ ) haloalkynyl, (C ３ -C ７ ) cycloalkyl, (C ４ -C １０ ) bicycloalkyl, (C ３ -C ７ ) heterocycloalkyl, halogenated (C ３ -C ７ ) heterocycloalkyl, (C ４ -C １０ ) heterobicycloalkyl, (C ４ -C １０ ) heterospiroalkyl, aryl, heteroaryl, -OR ａ , -SR ａ , -N(R ａ ) ２ , -COR ａ , -CO ２ R ａ , CON(R ａ ) ２ , -CN, -NC, NO ２ , N ３ , -SO ２ R ａ , -SO ２ N(R ａ ) ２ , -N(R ａ )SO ２ R ａ , 【Transformation 7】 selected from the group consisting of: V is absent, C(R ａ ) ２ , N.R. ａ , N(C=O)R ａ , NSO ２ R ａ or O; R ４ (C １ -C ６ ) alkyl, (C ３ -C ７ ) cycloalkyl, (C ４ -C １０ ) bicycloalkyl, (C ３ -C ７ ) heterocycloalkyl, (C ４ -C １０ ) heterobicycloalkyl, (C ４ -C １０ ) selected from the group consisting of heterospiroalkyl, aryl, and heteroaryl, each optionally containing one or more R ５ is substituted with; or alternatively V and R ４ are united (C ３ -C ７ ) heterocycloalkyl or (C ４ -C １０ ) forming a heterospiroalkyl; R ５ is independently in each occurrence H, D, halogen, (C １ -C ６ ) alkyl, (C １ -C ６ ) haloalkyl, (C ２ -C ６ ) alkenyl, (C ２ -C ６ ) haloalkenyl, (C ２ -C ６ ) alkynyl, (C ２ -C ６ ) haloalkynyl, (C ３ -C ７ ) cycloalkyl, (C ４ -C １０ ) bicycloalkyl, (C ３ -C ７ ) heterocycloalkyl, halogenated (C ３ -C ７ ) heterocycloalkyl, (C ４ -C １０ ) heterobicycloalkyl, (C ４ -C １０ ) heterospiroalkyl, aryl, heteroaryl, -OR ａ , -SR ａ , -N(R ａ ) ２ , -COR ａ , -CO ２ R ａ , CON(R ａ ) ２ , -CN, -NC, NO ２ , N ３ , -SO ２ R ａ , -SO ２ N(R ａ ) ２ , -N(R ａ )SO ２ R ａ , N(R ａ )COR ａ , 【Transformation 8】 selected from the group consisting of: R ａ is independently H in each case, (C １ -C ６ ) alkyl, (C ２ -C ６ ) alkenyl, (C ３ -C ７ ) cycloalkyl, aryl, or heteroaryl, or two R ａ are optionally taken together with halogen or (C １ -C ６ ) forming a 4- to 6-membered ring substituted with alkyl; A compound or a pharmaceutically acceptable salt thereof.

2. Q, T and U are each independently O, NH, NCH ３ , N(C=O)H, N(C=O)CH ３ , N(C=O)CH ２ CH ３ , NSO ２ CH ３ or NSO ２ CH ２ CH ３ 2. The compound of claim 1, wherein:

3. X １ , X ２ , X ３ , X ４ , X ５ , X ６ , X ７ , X ８ , X ９ , Y １ , Y ２ , Y ３ , Y ４ , Y ５ , Z １ , Z ２ , Z ３ , Z ４ and Z ５ 3. The compound of claim 1 or 2, wherein each is independently CH or N. 【Request Item 4】 【Chemistry 9】 but 【Chemistry 10】 The compound of any one of claims 1 to 3,

5. structural part 【Chemistry 11】 but 【Chemistry 12】 The compound of any one of claims 1 to 4, having the structure:

6. The compound of any one of claims 1 to 5, wherein n is 0, 1 or 2.

7. structural part 【Chemistry 13】 but 【Chemistry 14】 The compound of any one of claims 1 to 6, having the structure:

8. structural part 【Chemistry 15】 but 【Chemistry 16】 8. The compound of claim 7 having the structure: 【Request Item 9】 【Chemistry 17】 but [Chemistry 18] The compound of any one of claims 1 to 3,

10. structural part 【Chemistry 19】 but 【Chemistry 20】 The compound of any one of claims 1 to 3 and 9, having the structure:

11. 11. The compound of any one of claims 1 to 3 and 10, wherein n is 0, 1 or 2.

12. structural part 【Chemistry 21】 but 【Chemistry 22】 The compound of any one of claims 1 to 3 and 9 to 11, having the structure:

13. structural part 【Chemistry 23】 but 【Chemistry 24】 The compound of any one of claims 1 to 3 and 9 to 12, having the structure:

14. structural part 【Chemistry 25】 but 【Chemistry 26】 The compound of any one of claims 1 to 3 and 9 to 12, having the structure: 【Request Item 15】 【Chemistry 27】 but 【Chemistry 28】 The compound of any one of claims 1 to 3,

16. structural part 【Chemistry 29】 but 【Transformation 30】 16. The compound of any one of claims 1 to 3 and 15, having the structure:

17. structural part 【Chemistry 31】 but 【Chemistry 32】 The compound of any one of claims 1 to 3 and 15 to 16, having the structure:

18. 18. The compound of any one of claims 1 to 17, wherein Q is O.

19. Q is NR ａ , N(C=O)R ａ or NSO ２ R ａ The compound of any one of claims 1 to 17,

20. R １ is independently in each occurrence H, D, halogen, OR ａ , N(R ａ ) ２ , (C １ -C ６ ) alkyl, (C １ -C ６ ) alkynyl, (C ３ -C ７ ) heterocycloalkyl, (C ４ -C １０ ) heterospiroalkyl, halogenated (C ３ -C ７ ) heterocycloalkyl, aryl, (C ４ -C １０ ) Bicycloalkyl, -CN, -NC, N ３ , NO ２ , C.O.R. ａ , CO ２ R ａ , CON(R ａ ) ２ , -SO ２ R ａ or -SO ２ N(R ａ ) ２ where (C ３ -C ７ ) heterocycloalkyl optionally includes one or more (C １ -C ６ 20. The compound of any one of claims 1 to 19, substituted with alkyl.

21. R １ is independently in each occurrence H, halogen, (C １ -C ６ ) alkyl, (C ３ -C ７ ) heterocycloalkyl, (C ４ -C １０ ) heterospiroalkyl, halogenated (C ３ -C ７ ) heterocycloalkyl, N(R ａ ) ２ or —CN; ３ -C ７ ) heterocycloalkyl optionally includes one or more (C １ -C ６ 21. The compound of any one of claims 1 to 20, substituted with alkyl.

22. R １ is independently H in each case, (C １ -C ６ ) alkyl, (C １ -C ６ ) alkyl, halogenated (C ３ -C ７ ) heterocycloalkyl or (C ３ -C ７ ) heterocycloalkyl; ３ -C ７ ) heterocycloalkyl optionally includes one or more (C １ -C ６ 22. The compound of any one of claims 1 to 21, substituted with alkyl.

23. R １ is independently in each occurrence H, D, F, Cl, Br, CH ３ , OCH ３ , N.H. ２ , NHCH ３ , N(CH ３ ) ２ , 【Transformation 33】 The compound of any one of claims 1 to 22,

24. R １ is independently in each occurrence H, D, F, CH ３ , N.H. ２ , NHCH ３ , N(CH ３ ) ２ , 【Transformation 34】 The compound of any one of claims 1 to 23,

25. R １ At least one of 【Chemistry 35】 22. The compound of any one of claims 1 to 21, 【Request Item 26】 【Chemistry 36】 but 【Chemistry 37】 26. The compound of claim 25, wherein:

27. structural part 【Transformation 38】 but 【Chemistry 39】 【Chemistry 40】 【Chemistry 41】 25. The compound of any of claims 1-3, 10-14 and 18-24, having the structure: wherein Q is O or NH.

28. structural part 【Chemistry 42】 but 【Chemistry 43】 28. The compound of any of claims 1-3, 10-14, 18-25 and 27, having the structure: wherein Q is O or NH.

29. structural part 【Chemistry 44】 but 【Chemistry 45】 where Q is O or NH and R １ is H, (C １ -C ６ ) alkyl, (C ３ -C ７ ) heterocycloalkyl, halogenated (C ３ -C ７ 25. The compound of any one of claims 1 to 3 and 15 to 24, wherein: R is heterocycloalkyl or halogen.

30. structural part 【Chemistry 46】 but 【Chemistry 47】 30. The compound of any of claims 1-3, 15-24 and 29, having the structure: wherein Q is O or NH.

31. structural part 【Chemistry 48】 but 【Chemistry 49】 20. The compound of any one of claims 1 to 3, 5 to 8 and 14 to 19, having the structure: wherein Q is O or NH.

32. 2. The compound of claim 1 having the formula Ia:

33. structural part [Transformation 50] but 【Chemistry 51】 33. The compound of claim 1 or 32 having the structure:

34. structural part 【Chemistry 52】 but 【Chemistry 53】 34. The compound of any one of claims 1 and 32-33, having the structure:

35. R ２ is independently in each occurrence H, halogen, CH ３ , C.F. ３ , OH, NH ２ , -NHCH ３ or -N(CH ３ ) ２ The compound of any one of claims 1 and 32 to 34,

36. structural part 【Chemistry 54】 but 【Transformation 55】 36. The compound of any of claims 1 and 32-35, having the structure:

37. structural part 【Transformation 56】 but 【Chemistry 57】 37. The compound of claim 1 or any of claims 32-36, having the structure:

38. structural part 【Chemistry 58】 but 【Chemistry 59】 37. The compound of claim 1 or any of claims 32-36, having the structure:

39. structural part 【Transformation 60】 but 【Chemistry 61】 37. The compound of claim 1 or any of claims 32-36, having the structure:

40. structural part 【Transformation 62】 but 【Transformation 63】 40. The compound of any one of claims 1, 32-36 and 39, having the structure:

41. structural part 【Chemistry 64】 but 【Transformation 65】 41. The compound of any one of claims 1 and 32-40, having the structure:

42. structural part 【Chemical Formula 66】 but 【Transformation 67】 42. The compound of any one of claims 1 and 32-41, having the structure:

43. R ３ In each case, H, halogen, CH ３ , C.F. ３ , OH, NH ２ , -NHCH ３ or -N(CH ３ ) ２ 43. The compound of any one of claims 1 and 32 to 42,

44. substructure 【Transformation 68】 but 【Transformation 69】 44. The compound of any one of claims 1 and 32-43, having the structure:

45. structural part 【Transformation 70】 but 【Chemistry 71】 where R ３ H, CH ３ , OH, halogen or NH ２ and where R ｘ H, CH ３ or CH ２ CH ３ 45. The compound of any one of claims 1 and 32 to 44,

46. structural part 【Chemistry 72】 but 【Transformation 73】 where m is independently 1 or 2 in each occurrence and J is C(R ｙ ) ２ and R ｙ is independently H in each case, (C １ -C ６ ) alkyl, OH, O(C １ -C ６ ) alkyl or halogen.

47. structural part 【Chemistry 74】 but 【Chemistry 75】 wherein Y １ , Y ２ , Y ３ and Y ４ are each independently N, CH, or CCH ３ or CF.

48. structural part 【Transformation 76】 but 【Chemical 77】 where m is independently 1 or 2 in each occurrence and J is C(R ｚ ) ２ and R ｚ is independently H in each case, (C １ -C ６ ) alkyl, OH, O(C １ -C ６ ) alkyl or halogen.

49. structural part 【Transformation 78】 but 【Chemistry 79】 wherein Z １ , Z ２ , Z ３ and Z ４ are each independently N, CH, or CCH ３ or CF.

50. 10. The compound of claim 1 having the formula of Formula Ib:

51. structural part 【Chemistry 80】 but 【Chemistry 81】 where T and U are independently in each occurrence O, N, NR as allowed by valence. ａ , N(C=O)R ａ , NC(R ｂ ) ２ OP(=O)(OR ｂ ) ２ or NSO ２ R ａ 51. The compound of claim 1 or 50, wherein:

52. structural part 【Chemistry 82】 but 【Chemistry 83】 where R ３ H, CH ３ , OH, halogen or NH ２ and where R ａ H, CH ３ or CH ２ CH ３ 52. The compound of any one of claims 1 and 50 to 51,

53. structural part 【Chemical 84】 but 【Chemical 85】 52. The compound of any of claims 1 and 50-51, having the structure:

54. R ｂ is independently in each occurrence H or (C １ -C ６ 52. The compound of claim 49 or 51, wherein:

55. R ｂ is independently in each occurrence H, CH ３ , C.H. ２ CH ３ or CH(CH ３ ) ２ 55. The compound of claim 53 or 54, wherein:

56. 10. The compound of claim 1 having the formula of Formula Ic:

57. structural part 【Chemical 86】 but 【Chemistry 87】 where T and U are independently in each occurrence O, N, NR as allowed by valence. ａ , N(C=O)R ａ , NC(R ｂ ) ２ OP(=O)(OR ｂ ) ２ or NSO ２ R ａ 57. The compound of claim 1 or 56, wherein:

58. structural part 【Chemical 88】 but 【Chemistry 89】 where R ２ H, CH ３ , OH, halogen or NH ２ and where R ａ H, CH ３ or CH ２ CH ３ 58. The compound of any one of claims 1 and 56-57,

59. substructure 【Chemistry 90】 but 【Chemistry 91】 58. The compound of any of claims 1 and 56-57, having the structure:

60. R ｂ is independently in each occurrence H or (C １ -C ６ 60. The compound of claim 57 or 59, wherein:

61. R ｂ is independently in each occurrence H, CH ３ , C.H. ２ CH ３ or CH(CH ３ ) ２ 61. The compound of any one of claims 57 and 59 to 60,

62. R ２ is independently in each occurrence H, CH ３ , OH, NH ２ or halogen.

63. structural part 【Chemistry 92】 but 【Chemistry 93】 2. The compound of claim 1 having the structure:

64. structural part 【Chemical 94】 but 【Chemical 95】 2. The compound of claim 1 having the structure:

65. structural part 【Chemistry 96】 but 【Chemistry 97】 2. The compound of claim 1 having the structure:

66. structural part 【Chem.98】 V and R of ４ are united (C ４ -C １０ ) the compound of claim 1 which forms a heterospiroalkyl.

67. 2. The compound of claim 1, wherein V is absent.

68. R ４ But (C １ -C ６ ) alkyl, 【Chem.99】 68. The compound of any of claims 1 and 63-67, wherein m is an integer from 0 to 3.

69. R ５ is independently H in each case, (C １ -C ６ ) Alkyl, halogen, OR ａ , OH, NH ２ , N(R ａ )COR ａ , C.N., C.F. ３ , (C １ -C ６ ) haloalkyl or 【Chemistry 100】 and R ａ is independently H in each case, (C ２ -C ６ ) alkenyl or (C １ -C ６ ) alkyl.

70. structural part 【Chemistry 101】 but 【Chemical Engineering 102】 where V is C(R ａ ) ２ , O., N.R. ａ , N(C=O)R ａ or NSO ２ R ａ and V' is CR ａ or N.

71. R ５ is independently in each occurrence H, CH ３ , halogens, OH, CN, 【Chemistry 103】 CF ３ , (C １ -C ６ ) haloalkyl or NH ２ 71. The compound of claim 1 or 70, wherein:

72. R ａ is independently H in each case, (C ２ -C ６ ) alkenyl or (C １ -C ６ ) alkyl.

73. R ａ In each case, H, CH ３ or CH ２ CH ３ The compound of any one of claims 1, 19-20, 21, 51, 69 and 72,

74. structural part 【Chemical 104】 but 【Chemistry 105】 The compound of any one of claims 1, 63-66 and 68-73, having the structure:

75. structural part 【Chemistry 106】 but 【Chemistry 107】 The compound of any one of claims 1, 63 to 66, and 68 to 74, having the structure:

76. The compound of formula Ia 【Chemistry 108】 【Chemistry 109】 where R １ is H, (C １ -C ６ ) alkyl, N(R ａ ) ２ , (C ３ -C ７ ) heterocycloalkyl or halogen; R ５ and R １１ are each independently H or CH ３ and Y １ , Y ２ , Y ３ , Y ４ , Z １ , Z ２ , Z ３ , Z ４ , L １ and L ２ 33. The compound of claim 1 or 32, wherein each independently is CH or N; and V is NH or O.

77. R １ がH、F、Cl、Br、CH ３ 、CH ２ CH ３ 、CH(CH ３ ) ２ 、NH ２ 、NMe ２ 、 【Chemical 110】 77. The compound of claim 76, wherein:

78. The compound of formula Ib has the structure 【Chemistry 111】 where R １１ and R ５ are each independently H or CH ３ and Y １ , Y ２ , Y ３ , Y ４ , Z ２ , Z ３ and Z ４ 51. The compound of claim 1 or 50, wherein each is independently CH or N.

79. The compound of formula Ia 【Chemistry 112】 【Chemistry 113】 【Chemical 114】 【Chemical 115】 【Chemistry 116】 【Chemistry 117】 【Chemistry 118】 【Chemical 119】 【Chemical 120】 【Chemistry 121】 【Chemistry 122】 2. The compound of claim 1 having the formula:

80. The compound of formula Ib 【Chemical 123】 【Chemistry 124】 2. The compound of claim 1, wherein:

81. The compound of formula Ic 【Chemistry 125】 2. The compound of claim 1, wherein:

82. The compound 【Chemistry 126】 2. The compound of claim 1, wherein:

83. 10. The compound of claim 1, wherein the compound is selected from the group consisting of compounds 2-22 in Examples 2-22, respectively.

84. 84. A method of treating a disease in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any of claims 1-83.

85. 85. The method of claim 84, wherein the disease is selected from the group consisting of neurodegenerative diseases, cachexia, eating disorders, obesity, complications of obesity, inflammatory diseases, viral-induced inflammatory responses, Gulf War syndrome, tuberous sclerosis, retinitis pigmentosa, transplant rejection, cancer, autoimmune diseases, ischemic tissue injury, traumatic tissue injury, and combinations thereof.

86. 86. The method of claim 85, wherein the disease is a neurodegenerative disease.

87. 87. The method of claim 86, wherein the neurodegenerative disease is selected from the group consisting of Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, motor neuron disease, Huntington's disease, HIV-induced neurodegeneration, Lewy body disease, spinal muscular atrophy, prion disease, spinocerebellar ataxia, familial amyloidotic polyneuropathy, multiple sclerosis, and combinations thereof.

88. 86. The method of claim 85, wherein the disease is cachexia or an eating disorder.

89. 86. The method of claim 85, wherein the disease is obesity or a complication of obesity.

90. 90. The method of claim 89, wherein the complication of obesity is selected from the group consisting of glucose intolerance, fatty liver, dyslipidemia, and combinations thereof.

91. 86. The method of claim 85, wherein the disease is an inflammatory disease.

92. 92. The method of claim 91, wherein the inflammatory disease is selected from the group consisting of atopic dermatitis, allergies, asthma, and combinations thereof.

93. 86. The method of claim 85, wherein the disease is a viral-induced inflammatory response.

94. 94. The method of claim 93, wherein the virus-induced inflammatory response is SARS-induced inflammatory pneumonia, coronavirus disease 2019, or a combination thereof.

95. 86. The method of claim 85, wherein the disease is Gulf War syndrome or tuberous sclerosis complex.

96. 86. The method of claim 85, wherein the disease is retinitis pigmentosa or graft rejection.

97. 86. The method of claim 85, wherein the disease is ischemic tissue injury or traumatic tissue injury.

98. 86. The method of claim 85, wherein the disease is cancer.

99. 99. The method of claim 98, wherein the cancer is selected from the group consisting of adult T-cell leukemia / lymphoma, bladder, brain, breast, cervical, colorectal, esophageal, kidney, liver, lung, nasopharyngeal, pancreatic, prostate, skin, stomach, uterine, ovarian, and testicular cancer.

100. 99. The method of claim 98, wherein the cancer is leukemia.

101. 101. The method of claim 100, wherein the leukemia is adult T-cell leukemia / lymphoma.

102. 102. The method of claim 101, wherein the adult T-cell leukemia / lymphoma is caused by human T-cell lymphotropic virus.

103. 86. The method of claim 85, wherein the disease is an autoimmune disease.

104. Autoimmune diseases include achalasia, Addison's disease, adult Still's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, antiglomerular basement membrane disease, antitubular basement membrane nephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmune autonomic neuropathy, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease, autoimmune myocarditis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune urticaria, axonal and neuronal neuropathy, Barrow's disease, Behçet's disease, benign mucous membrane pemphigoid, pemphigoid, Castleman's disease, and Selenite. Riac's disease, Chagas' disease, chronic inflammatory demyelinating polyneuropathy, chronic relapsing multifocal osteomyelitis, Churg-Strauss syndrome, eosinophilic granulomatosis, cicatricial pemphigoid, Cogan's syndrome, cold agglutinin disease, congenital heart block, Coxsackie myocarditis, CREST syndrome, Crohn's disease, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus, Dressler's syndrome, endometriosis, eosinophilic esophagitis, eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, Evans' syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis), giant Myocarditis, glomerulonephritis, Goodpasture's syndrome, granulomatosis with polyangiitis, Graves' disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schonlein purpura, pemphigoid of pregnancy, hidradenitis suppurativa (acne inversa), hypogammaglobulinemia, IgA nephropathy, IgG4-related sclerosing disease, immune thrombocytopenic purpura, inclusion body myositis, interstitial cystitis, juvenile arthritis, juvenile diabetes mellitus (type 1 diabetes), juvenile myositis, Kawasaki disease, Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosus, lignified conjunctivitis, linear IgA disease, lupus, chronic Lyme disease, meningitis Yale's disease, microscopic polyangiitis, mixed connective tissue disease, Mooren's ulcer, Mukka-Habermann's disease, multifocal motor neuropathy, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neonatal lupus, neuromyelitis optica, neutropenia, ocular cicatricial pemphigoid, optic neuritis, relapsing rheumatism, pediatric autoimmune neuropsychiatric disorders, paraneoplastic cerebellar degeneration, paroxysmal nocturnal hemoglobinuria, Parry-Romberg syndrome, pars planitis (peripheral uveitis), Parsonage-Turner syndrome, pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia, POEMS syndrome, polyarteritis nodosa,Polyglandular syndrome type I, polyglandular syndrome type II, polyglandular syndrome type III, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, post-pericardiotomy syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, progestational dermatitis, psoriasis, psoriatic arthritis, pure red cell aplasia, pyoderma gangrenosum, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, relapsing polychondritis, restless legs syndrome, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, 104. The method of claim 103, wherein the disease is selected from the group consisting of Schmidt's syndrome, scleritis, scleroderma, Sjogren's syndrome, sperm and testicular autoimmunity, stiff-person syndrome, subacute bacterial endocarditis, Susac's syndrome, sympathetic ophthalmia, Takayasu's arteritis, temporal arteritis (giant cell arteritis), thrombocytopenic purpura, Tolosa-Hunt syndrome, transverse myelitis, ulcerative colitis, undifferentiated connective tissue disease, uveitis, vasculitis, leukoplakia, Vogt-Koyanagi-Harada disease, and combinations thereof.

105. 105. The method of any of claims 85-104, wherein the compound modulates Akt3 in immune cells.

106. 106. The method of claim 105, wherein the immune cells are selected from the group consisting of T cells, B cells, macrophages, and glial cells.

107. 107. The method of claim 106, wherein the glial cells are astrocytes, microglia, or oligodendrocytes.

108. 107. The method of claim 106, wherein the T cells are T regulatory cells.

109. 86. The method of claim 84 or 85, wherein the compound activates Akt3 signaling.

110. 86. The method of claim 84 or 85, wherein the compound inhibits Akt3 signaling.

111. 86. The method of claim 84 or 85, wherein the compound increases T regulatory cell activity or production.

112. 86. The method of claim 84 or 85, wherein the compound reduces T regulatory cell activity or production.

113. 113. The method of any of claims 84-112, further comprising administering to the subject a second therapeutic agent.

114. 114. The method of claim 113, wherein the second therapeutic agent is selected from the group consisting of nutritional supplementation, chemotherapy, anti-inflammatory agents, immunosuppressants, cholinesterase inhibitors, antidepressants, anxiolytics, antipsychotics, riluzole, edaravone, dopamine agonists, MAO B inhibitors, catechol O-methyltransferase inhibitors, anticholinergics, anticonvulsants, tetrabenazine, carbidopa-levodopa, antispasmodics, antibodies, fusion proteins, enzymes, nucleic acids, ribonucleic acids, antiproliferatives, cytotoxic agents, appetite stimulants, 5-HT3 antagonists, Cox-2 inhibitors, and combinations thereof.

115. 113. The method of any of claims 84-112, wherein the method further comprises treating the subject with an immunotherapeutic agent, an immunomodulator, a costimulatory activating agonist, a cytokine, a chemokine, a chemokine factor, an oncolytic virus, a biologic, a vaccine, a small molecule, a targeted therapy, an anti-inflammatory agent, a cell therapy, a chemotherapeutic agent, or radiation therapy.

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